1,4-benzodiazepinones and their uses as CCK antagonists

ABSTRACT

Benzodiazepine derivatives of the formula:  
                 
 
     wherein  
     R 1  is heterocyclic(lower)alkyl which may have one or more suitable substituent(s), etc.,  
     R 2  is lower alkyl, etc.,  
     R 3  is indolyl, etc.,  
     R 4  is hydrogen, etc.,  
     or a pharmaceutically acceptable salt thereof, which are useful as a medicament.

TECHNICAL FIELD

[0001] This invention relates to new benzodiazepine derivatives or apharmaceutically acceptable salts thereof which are useful as amedicament.

BACKGROUND ART

[0002] Some benzodiazepine derivatives have been known as described, forexample, in European Patent Application Publication No. 349949 andInternational Publication No. WO 96/04254.

DISCLOSURE OF INVENTION

[0003] This invention relates to new benzodiazepine derivatives orpharmaceutically acceptable salts thereof.

[0004] More particularly, it relates to new benzodiazepine derivativesand pharmaceutically acceptable salts thereof which are selectivecholecystokinin-B (CCK-B) antagonists or cholecystokinin-A and B(CCK-A/B) antagonists and therefore useful as therapeutical and/orpreventive agents for disorders of appetite regulatory systems (e.g.,anorexia, etc.), disorders associated with intestinal smooth musclehyperactivity (e.g., irritable bowel syndrome, sphincter spasm, etc.),panic disorder, psychosis (e.g., schizophrenia, etc.), pancreatitis,etc. and also useful as analgesics.

[0005] The benzodiazepine derivatives of this invention can berepresented by the following formula (I):

[0006] Wherein

[0007] R¹ is

[0008] (1) lower alkyl;

[0009] (2) hydroxy(lower)alkyl;

[0010] (3) protected hydroxy(lower)alkyl;

[0011] (4) heterocyclic(lower)alkyl which may have one or more suitablesubstituent(s);

[0012] (5) aryl(lower)alkyl which may have one or more suitablesubstituent(s);

[0013] (6) carboxy(lower)alkyl;

[0014] (7) protected carboxy(lower)alkyl; or

[0015] (8)

[0016] [wherein

[0017] A is lower alkylene and

[0018] R⁵ is

[0019] (a) lower alkyl,

[0020] (b) C₃-C₈ cycloalkyl,

[0021] (c) adamantyl,

[0022] (d) aryl which may have one or more suitable substituent(s),

[0023] (e) amino which may have one or two suitable substituent(s),

[0024] (f) azabicyclo[3.2.2]nonyl, or

[0025] (g) saturated heteromonocyclic group containing at least onenitrogen atom, which may have one or more suitable substituent(s)],

[0026] R² is

[0027] (1) lower alkyl,

[0028] (2) C₃-C₈ cycloalkyl,

[0029] (3) lower alkoxy(lower)alkyl,

[0030] (4) C₃-C₈ cycloalkyl(lower)alkyl,

[0031] (5) N,N-di(lower)alkylamino(lower)alkyl,

[0032] (6) lower alkylpiperazinyl(lower)alkyl,

[0033] (7) lower alkylthio(lower)alkyl,

[0034] (8) hydroxy(lower)alkyl,

[0035] (9) protected hydroxy(lower)alkyl,

[0036] (10) azabicyclo[3.2.2]nonyl(lower)alkyl,

[0037] (11) aryl which may have one or more suitable substituent(s),

[0038] (12) cyano,

[0039] (13) lower alkanoyl,

[0040] (14) carboxy(lower)alkenyl, or

[0041] (15) protected carboxy(lower)alkenyl,

[0042] R³ is indolyl or —NH-R⁶ [wherein R⁶ is

[0043] (1) aryl which may have one or more suitable substituent(s),

[0044] (2) pyridyl which may have one or more suitable substituent(s),or

[0045] (3)C₃-C₈ cycloalkyl], and

[0046] R⁴ is

[0047] (1) hydrogen,

[0048] (2) lower alkyl,

[0049] (3) halogen, or

[0050] (4) di(lower)alkylamino,

[0051] with proviso that when R⁴ is hydrogen, then R² is lower alkyl orC₃-C₈ cycloalkyl(lower)alkyl,

[0052] or a pharmaceutically acceptable salt thereof.

[0053] According to the present invention, the new benzodiazepinederivatives (I) can be prepared by the processes which are illustratedin the following scheme.

[0054] Process 1

[0055] Process 2

[0056] Process 3

[0057] Process 4

[0058] wherein R¹, R², R³, R⁴, and A are each as defined above,

[0059] is saturated heteromonocyclic group containing at least onenitrogen atom, which may have one or more suitable substituent(s),

[0060] X is halogen,

[0061] R⁷ is hydrogen, lower alkyl or hydroxy(lower)alkyl,

[0062] R⁸ is lower alkyl, hydroxy(lower)alkyl, aryl(lower)alkyl orpyridyl.

[0063] The starting compounds (II), (IV) and (VI) can be prepared by thefollowing processes.

[0064] Process A

[0065] Process B

[0066] Process C

[0067] Process D

[0068] Process E

[0069] wherein R¹, R², R³, R⁴, X,

[0070] and A are each as defined above,

[0071] R⁹ is protected amino, and

[0072] R¹⁰ is protected carboxy.

[0073] With regard to the object compound (I), in case that the compound(I) has the group of the formula:

[0074] in R¹, said group can also exist in the tautomeric form and suchtautomeric equilibrium can be represented by the following scheme.

[0075] Both of the above tautomeric isomers are included within thescope of the present invention. In the present specification and claim,the compounds including the group of such tautomeric isomers arerepresented for the convenient sake by one expression of the group ofthe formula (A).

[0076] Further, in case that the compound (I) has the group of theformula:

[0077] in R⁶, said group can also exist in the tautomeric from and suchtautomeric equilibrium can be represented by the following scheme.

[0078] Both of the above tautomeric isomers are included within thescope of the present invention. In the present specification and claim,the compounds including the group of such tautomeric isomers arerepresented for the convenient sake by one expression of the group ofthe formula (C).

BEST MODE FOR CARRYING OUT THE INVENTION

[0079] Suitable pharmaceutically acceptable salts of the object compound(I) are conventional non-toxic salts and include a metal salts such asan alkali metal salt (e.g., sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g., trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N′-dibenzylethylene diamine salt, etc.), an organic acid salt(e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate,formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acidsalt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), asalt with an amino acid (e.g., arginine, aspartic acid, glutamic acid,etc.), and the like.

[0080] In the above and subsequent descriptions of the presentspecification, suitable examples and illustrations of the variousdefinitions which the present invention include within the scope thereofare explained in detail as follows.

[0081] The term “lower” is intended to mean 1 to 6 carbon atom(s),unless otherwise indicated.

[0082] Suitable “lower alkyl” may include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, 3-methylbutyl, pentyl,t-pentyl, hexyl and the like.

[0083] Suitable “hydroxy protective group” in “protectedhydroxy(lower)alkyl” may include acyl, which includes aliphatic acylgroup and acyl group containing an aromatic or heterocyclic ring.

[0084] And, suitable examples of the said acyl may be lower alkanoyl(e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g.,mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,butanesulfonyl, etc.); arenesulfonyl (e.g., benzenesulfonyl, tosyl,etc.); aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl,indancarbonyl, etc.); ar(lower)alkanoyl (e.g., phenylacetyl,phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.

[0085] Suitable “heterocyclic group” may include saturated orunsaturated, monocyclic or polycyclic heterocyclic group containing atleast one hetero-atom such as an oxygen, sulfur, nitrogen atom and thelike. And especially preferable heterocyclic group may be heterocyclicgroup such as

[0086] unsaturated 3 to 8-membered heteromonocyclic group containing 1to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl and its N-oxide, pyperidyl, pyrimidinyl, pyrazinyl,dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.,1H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl(e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.),etc.,

[0087] saturated 3 to 8-membered heteromonocyclic group containing 1 to4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl,piperidino, piperazinyl, azacycloheptyl, azacyclooctyl, etc.,

[0088] unsaturated condensed heterocyclic group containing 1 to 5nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,isoindolinyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.,), dihydrotriazolopyridazinyl, etc.,;

[0089] unsaturated 3 to 8-membered heteromonocyclic group containing 1to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl,isoxazolyl, dihydroisoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 2,5-oxadiazolyl, etc.,), etc., saturated 3 to8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, morpholinyl, etc.,;

[0090] unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.,;

[0091] unsaturated 3 to 8-membered heteromonocyclic group containing 1to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,2,3-thiadiazolyl), etc.,;

[0092] saturated 3 to 8-membered heteromonocyclic group containing 1 to2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,thiazolidinyl, etc.,;

[0093] unsaturated 3 to 8-membered heteromonocyclic group containing anoxygen atom, for example furyl, etc.,

[0094] unsaturated 3 to 8-membered heteromonocyclic group containing asulfur atom, for example, thienyl, etc.,;

[0095] unsaturated condensed heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc., and the like.

[0096] Suitable “aryl” may include phenyl, naphthyl, and the like.

[0097] Suitable “protected carboxy” may include esterified carboxy andthe like.

[0098] Suitable example of the ester moiety of an esterified carboxy maybe the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester,propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butylester, pentyl ester, hexyl ester, etc.) which may have at least onesuitable substituent(s), for example, lower alkanoyloxy(lower)alkylester [e.g. acetoxymethyl ester, propionyloxymethyl ester,butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 1(or 2)-acetoxyethyl ester, 1(or 2 or3)-acetoxypropyl ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester, 1 (or2)-propionyloxyethyl ester, 1(or 2 or 3)-propionyloxypropyl ester, 1(or2)-butyryloxyethyl ester, 1(or 2)-isobutyryloxyethyl ester, 1(or2)-pivaloyloxyethyl ester, 1(or 2)-hexanoyloxyethyl ester,iso-butyryloxymethyl ester, 2-ethylbutyryloxymethyl ester,3,3-dimethylbutyryloxymethyl ester, 1(or 2)-pentanoyloxyethyl ester,etc.], lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester,etc.), mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethylester, 2,2,2-trichloroethyl ester, etc.), loweralkoxycarbonyloxy(lower)alkyl ester (e.g. methoxycarbonyloxymethylester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester,1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester,etc.), lower alkylthio(lower)alkyl ester (e.g. methylthiomethyl ester,1-(or 2-)methylthioethyl ester, 1-(or 2- or 3-)methylthiopropyl ester,1-(or 2- or 3- or 4-)methylthiobutyl ester, 1-(or 2- or 3- or 4- or5-)methylthiopentyl ester, 1-(or 2- or 3- or 4- or 5- or6-)methylthiohexyl ester, ethyl-thiomethyl ester, 1-(or2-)ethylthioethyl ester, 1-(or 2- or 3-)ethylthiopropyl ester,propylthiomethyl ester, 1-(or 2-)propylthioethyl ester, 1-(or 2- or3-)propylthiopropyl ester, etc.), phthalidylidene(lower)alkyl ester, or(5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester(e.g. vinyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester,propynyl ester, etc.); ar(lower)alkyl ester which may have at least onesuitable substituent(s) such as mono(or di or tri)phenyl(lower)alkylester which may have at least one suitable substituent(s) (e.g. benzylester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester,trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester,3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester,etc.); aryl ester which may have at least one suitable substituent(s)(e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenylester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidylester; and the like.

[0099] Suitable “lower alkylene” may include straight or branched onehaving 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamehylene, or the like, preferablyone having 1 to 4 carbon atom(s).

[0100] Suitable “C₃-C₈ cycloalkyl” may include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0101] Suitable “saturated heteromonocyclic group containing at leastone nitrogen atom” may include

[0102] saturated 3 to 8-membered heteromonocyclic group containing 1 to4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl,piperidino, piperidyl, piperazinyl, azacycloheptyl, azacyclooctyl,etc.,;

[0103] saturated 3 to 8-membered heteromonocyclic group containing 1 to2 oxygen alom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl,etc.,;

[0104] saturated 3 to 8-membered heteromonocyclic group containing 1 to2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,thiazolidinyl, etc., and the like.

[0105] Suitable “lower alkoxy” may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, and thelike.

[0106] Suitable “substituent” in the terms “heterocyclic(lower)alkylwhich may have one or more suitable substituent(s)”, “aryl(lower)alkylwhich may have one or more suitable substituent(s)”, “aryl which mayhave one or more suitable substituent(s)”, “amino which may have one ormore suitable substituent(s)”, “saturated heteromonocyclic groupcontaining at least one nitrogen atom, which may have one or moresuitable substituent(s)”, and “pyridyl which may have one or moresuitable substituent(s)” may include lower alkyl (which is exemplifiedabove), acyl (which is exemplified above), hydroxy, lower alkoxy (whichis exemplified above), carboxy(lower)alkoxy, protectedcarboxy(lower)alkoxy, nitro, amino, diacylamino, hydroxy(lower)alkyl,aryl(lower)alkyl, carbamoyl, oxo, aryl (which is exemplified above),mono or di substituted carbamoyl (which is exemplified above),heterocyclic group (which is exemplified below), heterocycliccarbonyl(lower)alkyl, halogen (e.g., chlorine, bromine, fluorine andiodine), lower alkylthio (e.g., methylthio, ethylthio, propylthio,butylthio, pentylthio, etc.), carboxy, protected carboxy (which isexemplified above), triphenyl(lower)alkyltetrazolyl,hydroxyimino(lower)alkyl (e.g., hydroxyiminomethyl, hydroxyiminoethyl,etc.), sulfo(lower)alkyl (e.g., sulfomethyl, sulfoethyl, etc.),tetrazolyl(lower)alkyl, di(lower)alkylamino (e.g., N,N-dimethylamino,etc.), and the like.

[0107] Suitable examples of the said mono or di substituted carbamoylmay be mono or di(lower)alkylcarbamoyl (e.g., methylcarbamoyl,dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl,N-methyl-N-ethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl,etc.), heterocyclic carbamoyl (e.g., tetrazolylcarbamoyl, etc.,), monoor di(carboxy)(lower)alkylcarbamoyl (e.g., carboxymethylcarbamoyl,1-carboxyethylcarbamoyl, 2-carboxyethylcarbamoyl,1,3-dicarboxypropylcarbamoyl,elc.,), mono or di (loweralkoxycarbonyl)(lower)alkylcarbamoyl (e.g.,1,3-diethoxycarbonylpropylcarbamoyl,etc.), mono or di (protectedcarboxy)(lower)alkylcarbamoyl (wherein “protected carboxy” isexemplified above), mono or di {(lower)alkyl}amino(lower)-alkylcarbamoyl(e.g., 2-dimethylaminoethylcarbamoyl, etc.), and the like.

[0108] Suitable “lower alkanoyl” may include formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.

[0109] Suitable “lower alkenyl” may include vinyl, propenyl, butenyl,pentenyl, hexenyl and the like.

[0110] Suitable “amino protective group” in “protected amino” mayinclude acyl (which is exemplified above) and the like.

[0111] The preferred embodiments of the object compound (I) are asfollows:

[0112] R¹ is

[0113] (1) lower alkyl;

[0114] (2) hydroxy(lower)alkyl;

[0115] (3) acyloxy(lower)alkyl;

[0116] (4) heterocyclic(lower)alkyl which may have one or moresubstituent(s) selected from the group consisting of lower alkyl andacyl;

[0117] (5) aryl(lower)alkyl which may have one or more acyl(s);

[0118] (6) carboxy(lower)alkyl;

[0119] (7) esterified carboxy(lower)alkyl; or

[0120] (8)

[0121] [wherein A is lower alkylene and

[0122] R⁵ is

[0123] (a) lower alkyl,

[0124] (b) C₃-C₈ cycloalkyl,

[0125] (c) adamantyl,

[0126] (d) aryl which may have one or more substituent(s) selected fromthe group consisting of lower alkyl, hydroxy, lower alkoxy,carboxy(lower)alkoxy, protected carboxy(lower)alkoxy, nitro, amino anddiacylamino,

[0127] (e) amino which may have one or two substituent(s) selected fromthe group consisting of lower alkyl, hydroxy(lower)alkyl,aryl(lower)alkyl and pyridyl,

[0128] (f) azabicyclo[3.2.2]nonyl, or

[0129] (g) saturated heteromonocyclic group containing at least onenitrogen atom, which may have one or more substituent(s) selected fromthe group consisting of carbamoyl, acyl, hydroxy, oxo, aryl,aryl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl,di(lower)alkylcarbamoyl, heterocyclic group, andheterocycliccarbonyl(lower)alkyl],

[0130] R² is

[0131] (1) lower alkyl,

[0132] (2) C₃-C₈ cycloalkyl,

[0133] (3) lower alkoxy(lower)alkyl,

[0134] (4) C₃-C₈ cycloalkyl(lower)alkyl,

[0135] (5) N,N-di(lower)alkylamino(lower)alkyl,

[0136] (6) lower alkylpiperazinyl(lower)alkyl,

[0137] (7) lower alkylthio(lower)alkyl,

[0138] (8) hydroxy(lower)alkyl,

[0139] (9) acyloxy(lower)alkyl,

[0140] (10)azabicyclo[3.2.2]nonyl(lower)alkyl,

[0141] (11) aryl which may have one or more halogen(s),

[0142] (12) cyano,

[0143] (13) lower alkanoyl,

[0144] (14) carboxy(lower)alkenyl, or

[0145] (15) esterified carboxy(lower)alkenyl,

[0146] R³ is indolyl or —NH-R⁶ [wherein R⁶ is

[0147] (1) aryl which may have one or more substituent(s) selected fromthe group consisting of lower alkyl, hydroxy, lower alkoxy, loweralkylthio, hydroxy(lower)alkyl, acyl, halogen, carboxy, protectedcarboxy, tetrazolyl, triphenyl(lower)alkyltetrazolyl,hydroxyimino(lower)alkyl, sulfo(lower)alkyl, tetrazolyl(lower)alkyl anddi(lower)alkylamino,

[0148] (2) pyridyl which may have one or more lower alkyl(s), or

[0149] (3) C₃-C₈ cycloalkyl],

[0150] R⁴ is

[0151] (1) hydrogen,

[0152] (2) lower alkyl,

[0153] (3) halogen or

[0154] (4) di(lower)alkylamino,

[0155] with proviso that when R⁴ is hydrogen, then R² is lower alkyl orC₃-C₈ cycloalkyl(lower)alkyl,

[0156] or a pharmaceutically acceptable salt thereof.

[0157] The more preferred embodiments of the object compound (I) are asfollows:

[0158] R¹ is

[0159] (1) lower alkyl;

[0160] (2) hydroxy(lower)alkyl;

[0161] (3) lower alkanoyloxy(lower)alkyl;

[0162] (4) heterocyclic(lower)alkyl which may have one or moresubstituent(s) selected from the group consisting of lower alkyl andlower alkanoyl;

[0163] (5) aryl(lower)alkyl which may have one or more loweralkanoyl(s);

[0164] (6) carboxy(lower)alkyl;

[0165] (7) lower alkoxycarbonyl(lower)alkyl; or

[0166] (8)

[0167] [wherein A is lower alkylene and

[0168] R⁵ is

[0169] (a) lower alkyl,

[0170] (b) C₃-C₈ cycloalkyl,

[0171] (c) adamantyl,

[0172] (d) aryl which may have one or more substituent(s) selected fromthe group consisting of lower alkyl, hydroxy, lower alkoxy,carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, nitro, aminoand di(lower alkanoyl)amino,

[0173] (e) amino which may have one or two substituent(s) selected fromthe group consisting of lower alkyl, hydroxy(lower)alkyl,phenyl(lower)alkyl and pyridyl,

[0174] (f) azabicyclo[3.2.2]nonyl, or

[0175] (g) saturated heteromonocyclic group containing at least onenitrogen atom, which may have one or more substituent(s) selected fromthe group consisting of carbamoyl, lower alkanoyl, hydroxy, oxo, phenyl,phenyl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl,di(lower)alkylcarbamoyl, piperidyl, pyridyl, pyrimidinyl andpyrrolidinylcarbonyl(lower)alkyl,

[0176] R² is

[0177] (1) lower alkyl,

[0178] (2) C₃-C₈ cycloalkyl,

[0179] (3) lower alkoxy(lower)alkyl,

[0180] (4) C₃-C₈ cycloalkyl(lower)alkyl,

[0181] (5) N,N-di(lower)alkylamino(lower)alkyl,

[0182] (6) lower alkylpiperazinyl(lower)alkyl,

[0183] (6) lower alkylpiperazinyl(lower)alkyl,

[0184] (7) lower alkylthio(lower)alkyl,

[0185] (8) hydroxy(lower)alkyl,

[0186] (9) lower alkanoyloxy(lower)alkyl,

[0187] (10)azabicyclo[3.2.2]nonyl(lower)alkyl, or

[0188] (11)aryl which may have one or more halogen(s),

[0189] (12)cyano,

[0190] (13)lower alkanoyl,

[0191] (14)carboxy(lower)alkenyl, or

[0192] (15)lower alkoxycarbonyl(lower)alkenyl,

[0193] R³ is indolyl or —NH-R⁶ [wherein R⁶ is

[0194] (1) aryl which may have one or more substituent(s) selected fromthe group consisting of lower alkyl, hydroxy, lower alkoxy, loweralkylthio, hydroxy(lower)alkyl, lower alkanoyl, halogen, carboxy,esterified carboxy, tetrazolyl, triphenyl(lower)alkyltetrazolyl,hydroxyimino(lower)alkyl, sulfo(lower)alkyl, tetrazolyl(lower)alkyl, anddi(lower)alkylamido,

[0195] (2) pyridyl which may have one or more lower alkyl(s), or

[0196] (3) C₃-C₈ cycloalkyl],

[0197] R⁴ is

[0198] (1) hydrogen,

[0199] (2) lower alkyl,

[0200] (4) di(lower)alkylamino,

[0201] with proviso that when R⁴ is hydrogen, then R² is lower alkyl orC₃-C₈ cycloalkyl(lower)alkyl,

[0202] or a pharmaceutically acceptable salt thereof.

[0203] And the more preferred embodiments of the object compound (I) areas follows:

[0204] wherein

[0205] R¹ is

[0206] (1) methyl,

[0207] (2) hydroxyethyl,

[0208] (3) acetoxyethyl,

[0209] (4) pyridylmethyl, imidazolylmethyl or thienylmethyl, each ofwhich may have one or more substituent(s) selected from the groupconsisting of methyl and acetyl,

[0210] (5) benzyl which may have one or more substituent(s) selectedfrom the group consisting of acetyl,

[0211] (6) carboxymethyl,

[0212] (7) ethoxycarbonylmethyl or t-butoxycarbonylmethyl, or

[0213] (8)

[0214] wherein A is methylene, and

[0215] R⁵ is

[0216] (a) methyl, ethyl or t-butyl,

[0217] (b) cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl,

[0218] (c) adamantyl,

[0219] (d) phenyl which may have one or more substituent(s) selectedfrom the group consisting of methyl, hydroxy, methoxy, carboxymethoxy,ethoxycarbonylmethoxy, nitro, amino and diacetylamino,

[0220] (e) amino which may have one or two substituent(s) selected fromthe group consisting of methyl, ethyl, t-butyl, isopropyl, hydroxyethyl,isobutyl, 1-methyl-1-phenylethyl and pyridyl,

[0221] (f) azabicyclo[3.2.2]nonyl, or

[0222] (g) pyrrolidinyl, piperidyl, azacycloheptyl, azacyclooctyl,piperazinyl or morpholinyl, each of which may have one or moresubstituent(s) selected from the group consisting of carbamoyl, acetyl,hydroxy, oxo, phenyl, benzyl, methyl, hydroxymethyl, hydroxyethyl,diethylcarbamoyl, piperidyl, pyridyl, pyrimidinyl andpyrrolidinylcarbonylmethyl],

[0223] R² is

[0224] (1) methyl, ethyl, isopropyl, isobutyl, butyl or isopentyl,

[0225] (2) cyclopropyl or cyclohexyl,

[0226] (3) methoxymethyl,

[0227] (4) cyclohexylmethyl,

[0228] (5) N,N-dimethylaminomethyl,

[0229] (6) methylpiperazinylmethyl,

[0230] (7) methylthiomethyl,

[0231] (8) hydroxymethyl,

[0232] (9) acetoxymethyl,

[0233] (10) (3-azabicyclo[3.2.2]non-3-yl)methyl,

[0234] (11) phenyl which may have one or more fluorine(s),

[0235] (12) cyano,

[0236] (13) formyl,

[0237] (14) carboxyvinyl, or

[0238] (15) ethoxycarbonylvinyl,

[0239] R³ is indolyl or —NH-R⁶ [wherein R⁶ is

[0240] (1) phenyl which may have one or more substituent(s) selectedfrom the group consisting of methyl, hydroxy, methoxy, methylthio,hydroxymethyl, formyl, acetyl, chlorine, bromine, carboxy,1-butoxycarbonyl, tetrazolyl, triphenylmethyltetrazolyl,hydroxyiminomethyl, hydroxyiminoethyl, sulfoethyl, tetrazolylmethyl andN,N-dimethylamino,

[0241] (2) pyridyl which may have one or more methyl(s), or

[0242] (3) cyclohexyl],

[0243] R⁴ is

[0244] (1) hydrogen,

[0245] (2) methyl, ethyl or isopropyl,

[0246] (3) chlorine, or

[0247] (4) N,N-dimethylamino, with proviso that when R⁴ is hydrogen,then R² is isopropyl, isobutyl, methyl, isopentyl, ethyl, butyl orcyclohexylmethyl,

[0248] or a pharmaceutically acceptable salt thereof.

[0249] And the more preferred embodiments of the object compound (I) areas follows:

[0250] wherein R² is lower alkyl or C₃-C₈ cycloalkyl,

[0251] R⁴ is lower alkyl,

[0252] R⁵ is C₃-C₈ cycloalkyl,

[0253] R⁶ is lower alkylphenyl and

[0254] A is lower alkylene,

[0255] or a pharmaceutically acceptable salt thereof.

[0256] And the most preferred embodiments of the object compound (I) areas follows:

[0257] where in R² is lower alkyl or C₃-C₈ cycloalkyl,

[0258] R⁴ is lower alkyl,

[0259] R⁵ is C₃-C₈ cycloalkyl,

[0260] R⁶ is lower alkylphenyl and

[0261] A is lower alkylene,

[0262] or a pharmaceutically acceptable salt thereof.

[0263] The processes for preparing the object compound (I) and thestarting compounds of the present invention are explained in detail inthe following.

[0264] Process 1:

[0265] The compound (I) or a salt thereof can be prepared by reactingthe compound (II) or its reactive derivative at the amino group or asalt thereof with the compound (III) or its reactive derivative or asalt thereof.

[0266] Suitable reactive derivative at the amino group of the compound(II) may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (II) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (II) with a silyl compound such asN,N-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like;a derivative formed by the reaction of the compound (II) with phosphorustrichloride or phosgene and the like.

[0267] Suitable reactive derivative of the compound (III) may include anacid halide, an acid anhydride, an activated amide, an activated ester,isocyanate, and the like. The suitable example may be an acid chloride,an acid azide; a mixed acid anhydride with an acid such as substitutedphosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoricacid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethylester, dimethyliminomethyl [(CH₃)₂N⁺═CH] ester, vinyl ester, propargylester, phenyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, pyranyl ester, pyridyl ester, piperidyl ester,etc.); an ester with a N-hydroxy compound (e.g.,N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphtalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); isocyanate of the formula:R³-N═C═O (in which R³ is as defined above), and the like. These reactivederivatives can optionally be selected according to the kind of thecompound (III) to be used.

[0268] Suitable salts of the compounds (II) and (III) can be referred tothe ones as exemplified for the compound (I).

[0269] The reaction is usually carried out in a conventional solventsuch as water, acetone, dioxane, acetonitrile, chloroform, methylenechloride, ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvents which donot adversely affect the reaction. These conventional solvents may alsobe used in a mixture with water.

[0270] When the compound (III) is used in free acid form or its saltform in the reaction, the reaction is preferably carried out in thepresence of a conventional condensing agent such asN,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N-diethylcarobodiimide, N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N′-carbonylbis-(2-methylimidazole); N,N′-carbonyldiimidazole,pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride; oxalyl chloride;triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

[0271] The reaction may also be carried out in the presence of aninorganic or organic base such as an alkali metal bicarbonate,tri(lower)alkylamine, pyridine, N-(lower)aklylmorphorine,N,N-di(lower)alkylbenzylamine, or the like. The reaction temperature isnot critical, and the reaction is usually carried out under cooling toheating.

[0272] The compound (III) or its reactive derivative, or a salt thereofcan be prepared in accordance with the method disclosed in thePreparations described later or similar manners thereto.

[0273] Process 2

[0274] The compound (I) or a salt thereof can be prepared by reactingthe compound (IV) or a salt thereof with a compound (V) or a saltthereof.

[0275] This reaction can be referred to that of Examples 3,6,8-10.

[0276] Process 3

[0277] The compound (Ia) or a salt thereof can be prepared by reactingthe compound (VI) or its reactive derivative at the carboxy group or asalt thereof with the compound (VII) or its reactive derivative at theimino group or a salt thereof.

[0278] Suitable reactive derivative at the carboxy group of the compound(VI) may include the same one as illustrated in the explanation of theProcess 1.

[0279] Suitable reactive derivative at the imino group of the compound(VII) may be adequately selected from the reactive derivative at theamino group that is illustrated in the explanation for the Process 1.

[0280] Suitable salts of the compounds (VI) and (VII) can be referred tothe ones as exemplified for the compound (1).

[0281] The reaction is usually carried out in the presence of base.

[0282] Suitable base may include an inorganic base such as alkali metalhydride (e.g., sodium hydride, etc.), alkali metal hydroxide (e.g.,sodium hydroxide, potassium hydroxide, etc.), alkaline earth metalhydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkalimetal carbonate (e.g., sodium carbonate, potassium carbonate, etc.),alkaline earth metal carbonate (e.g., magnesium carbonate, calciumcarbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate,potassium bicarbonate, etc.), alkali metal acetate (e.g., sodiumacetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g.,magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogenphosphate (e.g., disodium hydrogen phosphate, dipotassium hydrogenphosphate, etc.), or the like, and an organic base such as trialkylamine(e.g., trimethylamine, triethylamine etc.), picoline,N-methylpyrrolidine, N-methyl-morpholine, or the like.

[0283] The reaction is usually carried out in a solvent such as alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, diethyl ether or any other solvent which does notadversely affect the reaction.

[0284] The reaction temperature is not critical and the reaction isusually carried out under cooling to heating.

[0285] Process 4

[0286] The compound (Ib) or a salt thereof can be prepared by reactingthe compound (VI) or its reactive derivative at the carboxy group or asalt thereof with the compound (VIII) or its reactive derivative at theimino group or a salt thereof.

[0287] Suitable reactive derivative at the carboxy group of the compound(VI) and suitable reactive derivative at the imino group of the compound(VIII) may include the same one as illustrated in the explanation of theProcess 1.

[0288] Suitable salts of the compounds (VI) and (VIII) can be referredto the ones as exemplified for the compound (I).

[0289] The reaction can be referred to that of the aforementioned

[0290] Process 3.

[0291] It is to be noted that the compound (I) may include one or morestereoisomers due to asymmetric carbon atoms, and all of such isomersand mixture thereof are included within the scope of this invention. Itis also to be noted that the compound (I) may include a solvate, e.g.,hydrate, etc.

[0292] Process A

[0293] The compound (X) or a salt thereof can be prepared by reactingthe compound (IX) or a salt thereof with the compound (V) or a saltthereof. This reaction can be referred to that of aforementioned Process2.

[0294] Process B

[0295] The compound (Xa) or a salt thereof can be prepared by reactingthe compound (XI) or its reactive derivative at the carboxy group or asalt thereof with the compound (VII) or its reactive derivative at theimino group or a salt thereof. This reaction can be referred to that ofPreparation 59-5.

[0296] Process C

[0297] The compound (II) or a salt thereof can be prepared by subjectingthe compound (X) or a salt thereof to elimination reaction of the aminoprotective group. This elimination reaction can be referred to that ofPreparations 13-4, 15-2, 16-11 and 17-4.

[0298] Process D

[0299] The compound (VI) or a salt thereof can be prepared by subjectingthe compound (XII) or a salt thereof to elimination reaction of thecarboxy protective group. This elimination reaction can be referred tothat of Preparation 59-4.

[0300] Process E

[0301] The compound (IV) or a salt thereof can be prepared by reactingthe compound (XIII) or its reactive derivative at the amino group or asalt thereof with the compound (III) or its reactive derivative or asalt thereof.

[0302] The reaction can be referred to that of the aforementionedProcess 1.

[0303] The compound (XIII) or its reactive derivative at the amino groupor a salt thereof can be prepared in accordance with the methoddisclosed in the Preparations described later or similar mannersthereto.

[0304] The object compound (I) and pharmaceutically acceptable saltsthereof are selective CCK-B antagonists or CCK-A/B antagonists.

[0305] Further, it is expected that the object compound (I) andpharmaceutically acceptable salts thereof have gastrin antagonism and are useful as therapeutical and/or preventive agents for ulcers such asgastric ulcer, duodenal ulcer, excess gastric secretion,zollinger-Ellison Syndrome, non-ulcer dyspepsia, gastroesophageal refluxdisease, etc.

[0306] In order to s how the utility of the object compound (I),pharmacological activity of the representative compound thereof is shownin the following.

Experiment 1

[0307] [I] Test Compound

[0308] (1)N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylthiophenyl)urea

[0309] (2)N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-acetoxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0310] [II] Test:

[0311] [¹²⁵I]CCK-8 binding to guinea-pig cerebral cortical membranes

[0312] Test Method

[0313] (i) Membrane preparation

[0314] Guinea-pigs were killed by decapitation and bled to death.Cerebral cortex was removed, minced in a small quantity of 50 mMTris-HCl buffer (pH 7.4), and homogenized in 20 vol. of the buffer by aglass-teflon homogenizer. The homogenate was centrifuged at 30000 x g(160OOrpm) for 10 minutes. The pellet was then resuspended in the samebuffer by a glass-teflon homogenizer and recentrifuged at 30000 x g for10 minutes. This procedure (washings) was repeated twice more. The finalpellet (membrane) was suspended in incubation medium (see below) so asto obtain a final protein concentration of 4 mg/ml and frozen at −80° C.All manipulations were done at 0-4° C.

[0315] (ii) Receptor Binding Assay

[0316] The composition of incubation medium was as follows:

[0317] 10 mM HEPES (pH 6.5), 5 mM MgCl₂, 1 mM EGTA, 130 mM NaCl and 0.25mg/ml bacitracin. Frozen membranes were thawed and aliquots (400 μgprotein) were incubated for 60 minutes under shaking at 37° C. inplastic tubes in 500 μL of incubation medium with 50 pM ¹²⁵I-CCK-8 inthe presence or absence of test compound (1×10⁻⁸ M). To determine thenon-specific binding, CCK-8 at 1 μM was added. Each assay was performedin duplicate. Reaction mixture was filtered through a Whatman GF/B glassfilter to stop the reaction. After washing the filter with 50 mMTris-HCl (pH 7.4) buffer containing 0.1% BSA, the radioactivity of thefilter was countered. Non-specific binding was subtracted from totalbinding to yield specific binding. The effect of the test compound wasexpressed as % inhibition of specific ¹²⁵I-CCK-8 binding.

[0318] Test Result

[0319] Inhibition (%):

[0320] test compound(1): 97.3%

[0321] test compound(2): 97%

Experiment 2

[0322] [I] Test Compound

[0323] (A)N-[(3RS)-1-cyclohexylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0324] (B)N-[(3RS)-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0325] (C)N-[(3R)-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0326] (D)N-[(3RS)-1-cyclohexylcarbonylmethyl-5-cyclopropyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0327] [II] Tests:

[0328] Receptor binding studies and gastric emptying in mice

[0329] Test method

[0330] The tests were carried out in accordance with the methoddescribed at pages 571 to 572 in the following literature;

[0331] Harunobu Ito, Hajime Sogabe et al., The Journal of Pharmacologyand Experimental Therapeutics, 571, No.2, Vol.268 (1994).

[0332] Test results are shown in the table 1. TABLE 1 Biologicalevaluation results Com- IC₅₀ (nM) IC₅₀ (nM) selectivity Gastric emptyingpound for CCK-B for CCK-A A/B ID₅₀ (mg/Kg) (A) 3.7 1.1 0.30 0.4 (B) 1.60.9 0.56 0.4 (C) 1.0 0.3 0.30 0.23 (D) 1.1 2.0 1.82 1.8

[0333] The object compound (I) or pharmaceutically acceptable saltsthereof can usually be administered to mammals including human being inthe form of a conventional pharmaceutical composition such as capsule,micro-capsule, tablet, granule, powder, troche, syrup, aerosol,inhalation, solution, injection, suspension, emulsion, suppository orthe like.

[0334] The pharmaceutical composition of this invention can containvarious organic or inorganic carrier materials, which are conventionallyused for pharmaceutical purpose, such as excipient (e.g., sucrose,starch, mannit, sorbit, lactose, glucose, cellulose, talc, calciumphosphate, calcium carbonate, etc.), binding agent (cellulose, methylcellulose, hydroxypropyl cellulose, polypropylpyrrolidone, gelatin, gumarabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g.,starch, carboxymethyl cellulose, calcium salt of carboxymethylcellulose, hydroxypropylstarch, sodium glycole-starch, sodiumbicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g.,magnesium stearate, talc, sodium lauryrsulfate, etc.), flavoring agent(e.g., citric acid, menthol, glycine, orange powders, etc.),preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben,propylparaben, etc.), stabilizer (e.g., citric acid, sodium citrate,acetic acid, etc.), suspending agent (e.g., methyl cellulose,polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent,aqueous diluting agent (e.g., water), base wax (e.g., cacao butter,polyethyleneglycol, white petrolatum, etc.).

[0335] The effective ingredient may usually be administered with a unitdose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the abovedosage may be increased or decreased according to age, weight,conditions of the patient or the administering method.

[0336] The following Preparations and Examples are given only for thepurpose of illustrating the present invention in more detail.

Preparation 1-1

[0337] To a suspension of magnesium turnings (7.53 g) in dry ether (100ml) was added dropwise a solution of isopropyl bromide (36.87 g) in dryether (50 ml) at reflux temperature for 1 hour. The mixture was heatedat the same temperature for 1 hour and then allowed to cool to 5˜10° C.in an ice bath. To the mixture was added dropwise a solution of2-aminobenzonitrile (11.81 g) in dry tetrahydrofuran (100 ml) at thesame temperature for 1 hour. The mixture was stirred additionally 1 hourand then heated under reflux for 3 hours. The reaction mixture wasallowed to cool to 5˜10° C. in an ice bath. A 3N aqueous hydrochloricacid was added dropwise to the mixture for 1 hour and then heated underreflux for 3 hours. The resultant mixture was concentrated in vacuo toremove the organic solvent. The residue was extracted with chloroform(2×300 ml). The extracts were combined and washed with a brine(2×100ml). Dryness over magnesium sulfate and evaporation gave a crudeproduct. The product was purified by column chromatography on silica gelwith chloroform. The fractions containing the desired product werecombined and evaporated in vacuo to afford a pure2-isopropylcarbonylaniline (15.35 g) as a colorless oil.

[0338]¹H-NMR (CDCl₃, δ): 1.20 (6H, d, J=6.8Hz), 3.56-3.60 (1H, m), 6.30(2H, br), 6.63-6.67 (2H, m), 7.22-7.27 (1H, m) 7.77 (1H, d, J=12Hz)

Preparation 1-2

[0339] The following compound was prepared according to the method ofkatrisky [J. Org, Chem, 55, 2206 (1990)] in 84.6% yield.

[0340] 2-(1-benzotriazolyl)-2-benzyloxycarbonylaminoacetic acid

[0341]¹H-NMR (DMSO-d₆, δ): 5.01-5.13 (3H, m), 7.20-7.60 (7H, m), 8.00(1H, d, J=8.0Hz), 8.08 (1H, d, J=8.8Hz), 9.39 (1H, d, J=8.8Hz)

Preparation 1-3

[0342] To a suspension of 2-isopropylcarbonyl aniline (15.26 g) and2-(1-benzotriazolyl)-2-benzyloxycarbonylamino acetic acid (30.70 g) indry methylene chloride (200 ml) was added dropwise a solution ofdicyclohexyl carbodiimide (23.23 g) in dry methylene chloride (160 ml)at 20˜25° C. for 1 hour. The mixture was stirred at the same temperaturefor 1 hour. The resultant mixture was filtered by suction to remove aninsoluble material. The filtrate was concentrated in vacuo and theresidue was recrystallized from ethyl acetate and isopropyl ether togive 2-isopropylcarbonylN-{2-(1-benzotriazolyl)-2-benzyloxycarbonylamino}-acetylaniline (40.5 g)as a pale yellow powder.

[0343]¹H-NMR (DMSO-d₆, δ): 1.05 (6H, d, J=8.8Hz), 3.60-3.70 (1H, m),5.63 (2H, d, J=12.8Hz), 5.23 (1H, d, J=12.8Hz), 7.27-7.66 (9H, m),7.97-8.11 (3H, m), 8.37 (1H, d, J=8.4Hz), 9.65 (1H, d, J=8.0Hz), 12.08(1H, s)

Preparation 1-4

[0344] A suspension of2-isopropylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxycarbonylamino}acetylaniline(40.5 g) in methanol (150 ml) was treated with a saturated solution ofammonia in methanol (150 ml) at 0˜5° C. in an ice bath for 1 hour andthen at room temperature for 1 hour. The mixture was concentrated. Theresidue was treated with a 10% solution of ammonium acetate in aceticacid (300 ml) at room temperature for 2 hours. The resultant mixture wasevaporated in vacuo and the residue was partitioned between ethylacetate (100 ml) and 1N aqueous sodium hydroxide (10 ml). The organiclayer was washed with a saturated sodium hydrogen carbonate (100 ml) anda brine (100 ml). Dryness over magnesium sulfate and evaporationafforded a crude product. The crude product was recrystallized fromethyl acetate and isopropyl ether to give(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(26.88 g).

[0345]¹H-NMR (CDCl₃, δ): 0.92 (3H, d, J=6.8Hz), 1.28 (3H, d, J=6.8Hz),3.07-3.17 (1H, m), 5.12 (2H, s), 5.17 (1H, d, J=8.4Hz), 6.46(1H, d,J=8.4Hz), 7.11 (1H, d, J=8.4Hz), 7.22-7.40 (6H, m), 7.46 (1H, t,J=7.2Hz), 7.59 (1H, d, J=7.6Hz), 9.13 (1H, s)

Preparation 1-5

[0346] To a suspension of sodium hydride (0.123 g of a 65% dispersion inmineral oil) in dry N, N-dimethylformamide (10 ml) was added dropwise asolution of(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(1.00 g) in dry N, N-dimethylformamide (5 ml) under cooling in anice-bath. The mixture was stirred at the same temperature for 1 hour andthen at room temperature for 1 hour. To the mixture was added dropwise asolution of N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.77 g) indry N,N-dimethylformamide (5 ml) and stirred at the same condition for 2hours. The reaction mixture was concentrated in vacuo and the residuewas taken up with ethyl acetate (100 ml) and a saturated aqueous sodiumhydrogen carbonate (100 ml). The organic layer was washed with a brine(50 ml) and dried over anhydrous magnesium sulfate. Filtration andevaporation gave(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxy-carbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one.

[0347]¹H-NMR (CDCl₃, δ): 0.98 (3H, d, J=7.2Hz), 1.00-1.40 (2H, m), 1.31(3H, d, J=7.2Hz), 1.60-1.80 (6H, m), 2.04-2.16 (2H, m), 3.10-3.22 (1H,m), 3.44-3.86 (4H, m), 4.34 (1H, d, J=17.2Hz), 4.94 (1H, d, J=17.2Hz),5.04-5.20 (2H, m), 5.10 (1H, d, J=8.0Hz), 6.60 (1H, d, J=8.0Hz),7.20-7.60 (9H, m)

Preparation 1-6

[0348] Pd-C (5 wt %, 0.10g) was added to a suspension of(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.718 g) in methanol (20 ml) and then anmonium formate (0.351 g) atroom temperature. The mixture was stirred at the same condition for 4hours and filtered on Celite® to remove the catalyst. The filtrate wasconcentrated in vacuo and the residue was taken up with ethyl acetate(100 ml) and a saturated aqueous sodium hydrogen carbonate (50 ml). Theorganic layer was washed with a brine (50 ml) and dried over anhydroussodium sulfate. Filtration and evaporation gave(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.39 g) which was used in a following reaction step without furtherpurification.

[0349]¹H-NMR (CDCl₃, δ): 0.97 (3H, d, J=7.2Hz), 1.30-1.40 (2H, m), 1.31(3H, d, J=7.2Hz), 1.60-1.80 (6H, m), 2.00-2.20 (4H, m), 3.07-3.16 (1H,m), 3.47-3.89 (4H, m), 4.24 (1H, d, J=16.4Hz), 4.42 (1H, s), 5.00 (1H,d, J=16.4Hz), 7.20-7.53 (4H, m)

Preparation 2-1

[0350] To a suspension of Pd-C (5 wt %, 1.60 g) in methanol (60 ml) wasadded dropwise a solution of(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(8.00 g) in methanol (60 ml) and then ammonium formate (5.56 g) at roomtemperature. The reaction mixture was stirred at the same temperaturefor 1 hour. The catalyst was filtered on Celite®. The filtrate wasconcentrated in vacuo. The residue was taken up with ethyl acetate (100ml) and saturated aqueous sodium hydrogen carbonate (100 ml). Theorganic layer was washed with a brine (100 ml). Dryness over sodiumsulfate and evaporation gave(3RS)-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (4.21g). The product was used in a following reaction step without furtherpurification.

[0351]¹H-NMR (DMSO-d₆, δ): 0.79 (3H, d, J=7.2Hz), 1.20 (3H, d, J=7.2Hz),3.16-3.24 (1H, m), 3.20-3.50 (2H, br), 4.02 (1H, s), 7.14 (1H, d,J=8.0Hz), 7.19 (1H, t, J=7.2Hz), 7.48 (1H, t, J=7.2Hz), 7.69 (1H, d,J=7.2Hz), 10.44 (1H, s)

Preparation 2-2

[0352] To a solution of(3RS)-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (3.98g) in N,N-dimethylformamide (100 ml) was added 4-dimethylaminopyridine(0.20 g) and then dropwise a solution of di-tert-butyl dicarbonate (4.09g) in N,N-dimethylformamide (20 ml) at room temperature. The mixture wasstirred at ambient temperature overnight and concentrated in vacuo todryness. The residue was taken up with ethyl acetate (100 ml) and 1Naqueous hydrochloric acid (100 mI). The aqueous layer was separated,basified with sodium hydrogen carbonate and extracted with ethyl acetate(2×100 ml). The extracts were combined, dried over sodium sulfate andevaporated in vacuo to afford(3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(4.05 g). The product was used in a following reaction step withoutfurther purification.

[0353]¹H-NMR (CDCl₃, δ): 0.93 (3H, d, J=6.8Hz), 1.30 (3H, d, J=6.8Hz),1.45 (9H, s), 3.12-3.19 (1H, m), 5.15 (1H, d, J=8.4Hz), 6.22 (1H, d,J=8.4Hz), 7.12 (1H, d, J=8.0Hz), 7.23 (1H, t, J=8.0Hz), 7.46 (1H, t,J=8.0Hz), 7.58 (1H, d, J=8.0Hz), 8.97 (1H, br)

Preparation 2-3

[0354] To a suspension of sodium hydride (0.065 g of a 65% dispersion inmineral oil) in dry N,N-dimethylformamide (5 ml) was added dropwise asolution of(3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.508 g) in dry N,N-dimethylformamide (5 ml) under cooling in anice-bath. The mixture was stirred under the same condition for 30minutes and then at ambient temperature for 2 hours. To the mixture wasadded dropwise a solution of 2-acetyl-3-bromomethylthiophene (0.420 g)in dry N,N-dimethylformamide under cooling in an ice-bath. Aftercompletion of the addition, the mixture was stirred under the samecondition for 30 minutes and then at ambient temperature overnight. Theresultant mixture was concentrated in vacuo. The residue was treatedwith ethyl acetate (100 ml), washed with water (50 ml) and dried overanhydrous sodium sulfate. Filtration and evaporation gave a crudeproduct. The product was purified by column chromatography on silica gelwith an eluent of a mixture of chloroform and ethyl acetate (10:1) togive(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.380 g).

[0355]¹H-NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6.0Hz), 1.28 (3H, d, J=6.0Hz),1.46 (9H, s), 3.10-3.20 (1H, m), 5.22 (1H, d, J=9.6Hz), 5.33 (1H, d,J=17.2Hz), 5.66 (1H, d, J=17.2Hz), 6.31 (1H, d, J=8.8Hz), 6.93 (1H, d,J=4.8Hz), 7.20-7.30 (3H, m), 7.37-7.43 (2H, m), 7.50 (1H, d, J=8.0Hz)

Preparation 2-4

[0356] A solution of(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.370 g) in ethyl acetate (50 ml) was treated with gaseous hydrogenchloride at 5˜10° C. in an ice-bath for 30 minutes. The resultantmixture was extracted with 3N aqueous hydrochloric acid (2×10 ml). Theaqueous layer was basified with sodium hydrogen carbonate and extractedwith ethyl acetate (2×50 ml). The extracts were combined, over sodiumsulfate, filtered and concentrated in vacuo to afford(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.230 g), which was used in a following reaction step without furtherpurification.

[0357]¹H-NMR (CDCl₃, δ): 0.88 (3H, d, J=6.8Hz), 1.29 (3H, d, J=6.8Hz),2.50 (3H, s), 3.08-3.18 (1H, m), 3.25 (1H, br), 4.43 (1H, s), 5.37 (1H,d, J=17.2Hz), 5.67 (1H, d, J=17.2Hz), 6.92 (1H, d, J=5.2Hz), 7.20-7.50(6H, m)

Preparation 3

[0358] To a solution of(3RS)-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.536g) in methylene chloride (30 ml) was added dropwise a solution of3-methylphenyl isocyanate (0.361 g) in methylene chloride (5 ml) at roomtemperature for 10 minutes. The mixture was stirred at the samecondition for 2 hours. The resultant precipitate was collected bysuction to affordN-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(0.600 g). The filtrate was concentrated in vacuo and the residue wastreated with isopropyl ether to give the second crop of the desiredcompound (0.170 g).

[0359]¹H-NMR (DMSO-d₆, δ): 0.81 (3H, d, J=6.8Hz), 1.18 (3H, d, J=6.8Hz),2.23 (3H, s), 3.20-3.30 (1H, m), 4.49 (1H, d, J=8.0Hz), 6.72 (1H, d,J=8.0Hz), 7.06-7.22 (6H, m), 7.55 (1H, t, J=7.2Hz), 7.77 (1H, d,J=7.2Hz), 8.88 (1H, s), 10.69 (1H, s)

Preparation 4

[0360] To a solution of 3-aminoacetophenone (2.049 g) and pyridine(1.286 g) in tetrahydrofuran (35 ml) was added dropwise a solution of4-nitrophenylchloroformate (3.288 g) in tetrahydrofuran (10 ml) undercooling in an ice bath. After completion of the addition, the mixturewas allowed to stand to ambient temperature and stirred over night.Water was added to the mixture. The resultant precipitate was collectedby suction filtration, washed with water and dried in vacuo at 80° C. toafford 4-nitrophenyl N-(3-acetylphenyl)carbamate (3.31 g).

[0361]¹H-NMR (DMSO-d₆, δ): 2.57 (3H, s), 7.50-7.59 (3H, m), 7.71 (1H, d,J=8.0Hz), 7.76 (1H, d, J=8.0Hz), 8.13 (1H, s), 8.32 (2H, d, J=9.0Hz),10.67 (1H, s)

Preparation 5

[0362] The following compound was prepared in a similar manner to thatof preparation 4.

[0363] 4-nitrophenyl N-{3-(tetrazol-5-yl)phenyl}carbamate

Preparation 6-1

[0364] The following compound was prepared in a similar manner to thatof Preparation 1-1.

[0365] 2-(2-methyl)propylcarbonylaniline

[0366]¹H-NMR (CDCl₃, δ): 0.93 (6H, q, J=8Hz), 2.04-2.12 (1H, m), 2.93(2H, d, J=8Hz), 6.26 (2H, br), 6.60 (2H, d, J=8Hz), 7.24 (1H, t, J=8Hz),7.74 (1H, d, J=8Hz)

Preparation 6-2

[0367] The following compound was prepared in a similar manner to thatof Preparation 1-3.

[0368]2-(2-methyl)propylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxylcarbonylamino}acetylaniline

[0369]¹H-NMR (CDCl₃, δ): 0.83 (6H, q, J=8Hz), 2.02-2.10 (1H, m), 2.70(2H, d, J=8Hz), 5.04-5.14 (3H, m), 6.95 (1H, br), 7.13-7.45 (9H, m),7.84 (2H, d, J=8Hz), 8.08 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz). 12.40(1H, br)

Preparation 6-3

[0370] A solution of2-(2-methyl)propylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzloxycarbonylamino}acetylaniline(31.7 g) in methanol (100 ml) was treated with a saturated solution ofammonia in methanol (200 ml) at 0° C. in a dry ice-acetone bath for 1hour and then stirred overnight at ambient temperature. The resultantmixture was concentrated and the residue was treated with a 0.5N aqueoussodium hydroxide and chloroform. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to give a crude compound.The crude compound was purified by a column chromatography on silica gelwith a mixture of chloroform and ethyl acetate to give(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(2-methylpropyl)-1H-1,4-benzodiazepin-2-oneas a colorless powder.

[0371]¹H-NMR (CDCl₃, δ): 0.71 (3H, d, J=8Hz), 0.83 (3H, d, J=8Hz),1.21-1.76 (1H, m), 2.45 (1H, dd, J=16Hz, J=16Hz), 2.85 (1H, dd, J=8Hz,J=16Hz), 5.07-5.21 (3H, m), 6.68 (1H, d, J=8Hz), 7.14-7.53 (9H, m), 7.87(1H, d, J=8Hz)

Preparation 6-4

[0372] The following compound was prepared in a similar manner to thatof Preparation 2-1.

[0373](3RS)-3-amino-2,3-dihydro-5-(2-methylpropyl)-1H-1,4-benzodiazepin-2-one

[0374]¹H-NMR (CDCl₃, δ): 0.76 (3H, d, J=8Hz), 0.84 (3H, d, J=8Hz),1.74-1.83 (1H, m), 2.20 (2H, br), 2.46 (1H, dd, J=16Hz, J=16Hz), 2.85(1H, dd, J=8Hz, J=16Hz), 4.32 (1H, s), 7.14 (1H, d, J=8Hz), 7.24 (1H, t,J=8Hz), 7.46 (1H, d, J=8Hz), 7.56 (1H, d, J=8Hz), 9.04 (1H, s)

Preparation 6-5

[0375] The following compound was prepared in a similar manner to thatof Preparation 3.

[0376] N-[(3 RS)-2,3-dihydro-5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0377]¹H-NMR (DMSO-d₆, δ): 0.68 (3H, d, J=8Hz), 0.84 (3H, d, J=8Hz),1.66-1.70 (1H, m), 2.23 (3H, s), 2.34 (1H, dd, J=16Hz, J=16Hz), 2.94(1H, dd, J=8Hz, J=16Hz), 4.99 (1H, d, J=14Hz), 6.72 (1H, d, J=8Hz),7.07-7.30 (7H, m), 7.55 (1H, t, J=8Hz), 7.76 (1H, d, J=14Hz), 8.85 (1H,s)

Preparation 7-1

[0378] The following compound was prepared in a similar manner to thatof Preparation 2-2.

[0379](3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-methylpropyl)-1H-1,4-benzodiazepin-2-one

[0380]¹H-NMR (CDCl₃, δ): 0.72 (3H, d, J=8Hz), 0.86 (3H, d, J=8Hz), 1.45(9H, s), 1.78-1.82 (1H, m), 2.64 (1H, d, J=16Hz), 2.88 (1H, d, J=8Hz,16Hz), 5.14 (1H, d, J=8Hz), 6.35 (1H, d, J=8Hz), 7.21-7.57 (4H, m), 9.71(1H, s)

Preparation 7-2

[0381] The following compound was prepared in a similar manner to thatof Preparation 2-3.

[0382](3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-methylpropyl)-1H-1,4-benzodiazepin-2-one

[0383]¹H-NMR (CDCl₃, δ): 0.76 (3H, d, J=8Hz), 0.88 (3H, d, J=8Hz), 1.42(9H, s), 1.61-1.88 (9H, m), 2.10 (2H, br), 2.48 (1H, dd, J=16Hz,J=16Hz), 2.89 (1H, dd, J=8Hz, J=16Hz), 3.44-3.96 (4H, m). 4.14 (1H, d,J=18Hz), 5.02 (1H, d, J=18Hz), 5.25 (1H, d, J=8Hz), 6.43 (1H, d, J=8Hz),7.24-7.54 (4H, m)

Preparation 7-3

[0384] The following compound was prepared in a similar manner to thatof Preparation 2-4.

[0385](3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-methylpropyl)-1H-1,4-benzodiazepin-2-one

[0386]¹H-NMR (CDCl₃, δ): 0.77 (3H, d, J=8Hz), 0.88 (3H, d, J=8Hz),1.70-2.11 (13H, m), 2.50 (1H, dd, J=16Hz, J=16Hz), 2.88 (1H, dd, J=8Hz,J=16Hz), 3.46-3.92 (4H, m). 4.10 (1H, d, J=18Hz), 4.43 (1H, s), 5.06(1H, d, J=18Hz), 7.21-7.51 (4H, m)

Preparation 8-1

[0387] The following compound was prepared in a similar manner to thatof Preparation 1-3.

[0388]2-methylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxycarbonylamino}acetylaniline

[0389]¹H-NMR (CDCl₃, δ): 2.53 (3H, s), 5.04-5.26 (3H, m),7.07-7.52 (10H,m), 7.78-7.87 (2H, m), 8.05 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz), 12.36(1H, s)

Preparation 8-2

[0390] The following compound was prepared in a similar manner to thatof Preparation 6-3.

[0391](3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-methyl-1H-1,4-benzodiazepin-2-one

[0392]¹H-NMR (CDCl₃, δ): 2.42 (3H, s), 5.05-5.15 (3H, m), 6.82 (1H, d,J=8Hz), 7.08 (1H, d, J=8Hz), 7.08-7.34 (7H, m), 7.52 (1H, d, J=8Hz),10.13 (1H, s)

Preparation 8-3

[0393] The following compound was prepared in a similar manner to thatof Preparation 2-1.

[0394] (3RS)-3-amino-2,3-dihydro-5-methyl-1H-1,4-benzodiazepin-2-one

[0395]¹H-NMR (CDCl₃, δ): 2.35-2.64 (2H, br), 2.45 (3H, s), 4.32 (1H, s),7.18 (1H, d, J=8Hz), 7.21 (1H, t, J=8Hz), 7.45 (1H, t, J=8Hz), 7.58 (1H,d, J=8Hz), 9.60 (1H, br)

Preparation 8-4

[0396] The following compound was prepared in a similar manner to thatof Preparation 3.

[0397]N-[(3RS)-2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0398]¹H-NMR (DMSO-d₆, δ): 2.23 (3H, s), 2.40 (3H, s), 4.95 (1H, d,J=8Hz), 6.72 (1H, d, J=8Hz), 7.08-7.31 (6H, m), 7.56 (1H, t, J=8Hz),7.78 (1H, d, J=8Hz), 8.88 (1H, s), 10.77 (1H, s)

Preparation 9-1

[0399] The following compound was prepared in a similar manner to thatof Preparation 1-1.

[0400] 2-(3- methyl)butylcarbonylaniline

[0401]¹H-NMR (CDCl₃, δ): 0.94 (6H, q, J=8Hz), 1.62 (2H, q, J=8Hz),2.06-2.10 (1H, m), 2.93 (2H, t, J=8Hz), 6.26 (2H, br), 6.63 (2H, d,J=8Hz), 7.24 (1H, t, J=8Hz), 7.74 (1H, d, J=8Hz)

Preparation 9-2

[0402] The following compound was prepared in a similar manner to thatof Preparation 1-3.

[0403]2-(3-methyl)butylcarbonyl-N-[2-(1-benzotriazolyl)-2-benzyloxylcarbonylamino]acetylaniline

[0404]¹H-NMR (CDCl₃, δ): 0.88 (6H, q, J=8Hz), 1.44 (2H, q, J=8Hz),1.80-1.84 (1H, m), 2.40 (2H, t, J=8Hz), 5.05-5.28 (3H, m), 6.97 (1H,br), 7.26-7.57 (9H, m), 7.85 (2H, d, J=8Hz), 8.08 (1H, d, J=8Hz), 8.63(1H, d, J=8Hz), 12.40 (1H, br)

Preparation 9-3

[0405] The following compound was prepared in a similar manner to thatof Preparation 6-3.

[0406](3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(3-methylbutyl)-1H-1,4-benzodiazepin-2-one

[0407]¹H-NMR (CDCl₃, δ): 0.83-0.86 (6H, m), 1.29-1.53 (3H, m), 2.74-2.79(2H, m), 4.69 (1H, s), 5.08-5.17 (3H, m), 6.52 (1H, d, J=8Hz), 7.09 (1H,d, J=8Hz), 7.23-7.36 (5H, m), 7.44 (1H, t, J=8Hz), 7.57 (1H, d, J=8Hz),9.26 (1H, s)

Preparation 9-4

[0408] The following compound was prepared in a similar manner to thatof Preparation 2-1.

[0409] (3RS)-3-amino-2,3-dihydro-5-(3-methylbutyl)-1H-1,4-benzodiazepin-2-one

[0410]¹H-NMR (CDCl₃, δ): 0.83 (3H, dd, J=3.5Hz, J=4.9Hz), 0.88 (3H, dd,J=1.4Hz, J=2.8Hz), 1.30-1.42 (1H, m), 1.45-1.60 (2H, m), 2.72-2.76 (2H,m), 3.40-3.78 (2H, br), 4.23 (1H, s), 7.02-7.75 (4H, m), 9.70 (1H, br)

Preparation 9-5

[0411] The following compound was prepared in a similar manner to thatof Preparation 3.

[0412]N-[(3RS)-2,3-dihydro-5-(3-methylbutyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0413]¹H-NMR (CDCl₃, δ): 0.73 (6H, t, J=8Hz), 1.15-1.40 (3H, m), 2.25(3H, s), 2.6-2.72 (2H, m), 5.35 (1H, d, J=16Hz), 6.78 (1H, d, J=8Hz),7.07-7.32 (7H, m), 7.50 (1H, d, J=8Hz), 7.78 (1H, d, J=14Hz), 8.80 (1H,br)

Preparation 10-1

[0414] The following compound was prepared in a similar manner to thatof Preparation 1-1.

[0415] 2-ethylcarbonylaniline

[0416]¹H-NMR (CDCl₃, δ): 1.20 (3H, t, J=7.0Hz), 2.97 (2H, q, J=7.0Hz),6.27 (2H, br), 6.62-6.66 (2H, m), 7.22-7.27 (1H, m), 7.75 (1H, d, J=8Hz)

Preparation 10-2

[0417] The following compound was prepared in a similar manner to thatof Preparation 1-3.

[0418]2-ethylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxycarbonylamino}acetylaniline

[0419]¹H-NMR (CDCl₃, δ): 1.06 (3H, t, J=7.0 Hz), 2.94 (2H, q, J=7.0Hz),5.06-5.25 (3H, m), 6.96 (1H, br), 7.14-7.42 (7H, m), 7.52-7.56 (2H, m),7.86-7.88 (2H, m), 8.93 (1H, d, J=8.0Hz), 8.63 (1H, d, J=8.0Hz), 12.45(1H, s)

Preparation 10-3

[0420] The following compound was prepared in a similar manner to thatof Preparation 6-3.

[0421](3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-1H-1,4-benzodiazepin-2-one

[0422]¹H-NMR (CDCl₃, δ): 1.08 (3H, t, J=7.0Hz), 2.74-2.86 (2H, m),5.08-5.16 (2H, m), 5.18 (1H, d, J=8.0Hz), 6.52 (1H, d, J=8.0Hz), 7.12(1H, d, J=8.0Hz), 7.23-7.38 (6H, m), 7.47 (1H, t, J=8.0Hz), 7.58 (1H, d,J=8.0Hz), 9.27 (1H, s)

Preparation 10-4

[0423] The following compound was prepared in a similar manner to thatof Preparation 2-1.

[0424] (3RS)-3-amino-2,3-dihydro-5-ethyl-1H-1,4-benzodiazepin-2-one

[0425]¹H-NMR (CDCl₃, δ): 1.10 (3H, t, J=7.0Hz), 2.00 (2H, br), 2.73-2.83(2H, m), 4.33 (1H, s), 7.10 (1H, d, J=8.0Hz), 7.23 (1H, t, J=8.0Hz),7.46 (1H, t, J=8.0Hz), 7.57 (1H, d, J=8.0Hz), 8.74 (1H, s)

Preparation 1 0-5

[0426] The following compound was prepared in a similar manner to thatof Preparation 3.

[0427]N-[(3RS)-2,3-dihydro-5-ethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[0428]¹H-NMR (DMSO-d₆, δ): 0.99 (3H, t, J=7.0Hz), 2.23 (3H, s),2.66-2.72 (1H, m), 2.84-2.88 (1H, m), 5.00 (1H, d, J=8.0Hz), 6.72 (1H,d, J=7.0Hz), 7.07-7.30 (6H, m), 7.55 (1H, d, J=7.0Hz), 7.78 (1H, d,J=8.0Hz), 8.88 (1H, s), 10.73 (1H, s)

Preparation 11-1

[0429] The following compound was prepared in a similar manner to thatof Preparation 1-1.

[0430] 2-(3-butenyl)carbonylaniline

[0431]¹H-NMR (CDCl₃, δ): 2.46-2.50 (2H, m), 3.03 (2H, t, J=7Hz), 5.01(1H, d, J=13.0Hz), 5.09 (1H, d, J=18.8Hz), 5.86-5.98 (1H, m), 6.26 (2H,br), 6.62-6.66 (2H, m), 7.25 (1H, t, J=8.4Hz), 7.75 (1H, d, J=8.0Hz)

Preparation 11-2

[0432] The following compound was prepared in a similar manner to thatof Preparation 1-4 and Preparation 1-5.

[0433](3RS)-3-benzyloxycarbonylamino-5-(3-butenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[0434]¹H-NMR (CDCl₃, δ): 2.24-2.36 (2H, m), 2.88 (2H, t, J=7.6Hz),4.90-5.19 (5H, m), 5.71-5.80 (1H, m), 6.65 (1H, d, J=8.0Hz), 7.12 (1H,d, J=7.6Hz), 7.25-7.36 (6H, m), 7.49 (1H, t, J=7.6Hz), 7.59 (1H, d,J=7.6Hz), 9.17 (1H, br)

Preparation 11-3

[0435] The following compound was prepared in a similar manner to thatof Preparation 1-6.

[0436] (3RS)-3-amino-5-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[0437]¹H-NMR (DMSO-d₆, δ): 0.82 (3H, t, J=7.2Hz), 1.16-1.20 (2H, m),1.26-1.40 (2H, m), 2.40 (2H, br), 2.60-2.68 (1H, m), 2.76-2.81 (1H, m),3.27 (1H, s), 7.14 (1H, d, J=8.0Hz), 7.19 (1H, t, J=8.0Hz), 7.48 (1H, t,J=8.0Hz), 7.67 (1H, d, J=8.0Hz), 10.47 (1H, br)

Preparation 11-4

[0438]

[0439] The following compound was prepared in a similar manner to thatof Preparation 2-2.

[0440] (3RS)-3-tert-butoxycarbonylamino-5-butyl-2,3-dihydro-1H1,4-benzodiazepin-2-one

[0441]¹H-NMR (CDCl₃, δ): 0.84 (3H, t, J=7.6Hz), 1.24-1.29 (2H, m),1.40-1.47 (2H, m), 1.44 (9H, s), 2.73-2.90 (2H, m), 5.14 (1H, d,J=8.0Hz), 6.28 (1H, d, J=8.0Hz), 7.11 (1H, d, J=8.0Hz), 7.24 (1H, t,J=8.0Hz), 7.47 (1H, t, J=8.0Hz), 7.57 (1H, d, J=8.0Hz), 8.97 (1H, br)

Preparation 11-5

[0442] The following compound was prepared in a similar manner to thatof Preparation 2-3.

[0443](3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxycarbonylamino-5-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[0444]¹H-NMR (CDCl₃, δ): 0.86 (3H, t, J=7.6Hz), 1.24-1.31 (2H, m), 1.42(9H, s), 1.42-1.52 (2H, m), 1.60-1.80 (8H, m), 2.05-2.15 (2H, m),2.70-2.90 (2H, m), 3.45-3.90 (4H, m), 4.27 (1H, d, J=16.0Hz), 4.94 (1H,d, J=16.0Hz), 5.24 (1H, d, J=8.0Hz), 6.41 (1H, d, J=8.0Hz), 7.23-7.54(4H, m)

Preparation 11-6

[0445] The following compound was prepared in a similar manner to thatof Preparation 2-4.

[0446](3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[0447]¹H-NMR (CDCl₃, δ): 0.86 (3H, t, J=7.6Hz), 1.24-1.31 (2H, m),1.44-1.80 (12H, m), 2.00-2.15 (2H, m), 2.70-2.90 (2H, m), 3.40-3.90 (4H,m), 4.26 (1H, d, J=16.0Hz), 4.40 (1H, s), 4.94 (1H, d, J=16.0Hz),7.20-7.60 (4H, m)

Preparation 12-1

[0448] The following compound was prepared in a similar manner to thatof Preparation 1-1.

[0449] 2-cyclohexylmethylcarbonylaniline

[0450]¹H-NMR (CDCl₃, δ): 0.80-1.40 (6H, m), 1.60-1.80 (4H, m), 1.85-2.00(1H, m), 2.77 (2H, d, J=6.8Hz), 6.28 (1H, br), 6.62-6.67 (2H, m),7.23-7.27 (1H, m), 7.73 (1H, d, J=8.4Hz)

Preparation 12-2

[0451] The following compound was prepared in a similar manner to thatof Preparation 1-2.

[0452]2-cyclohexylmethylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxycarbonylamino}acetylaniline

[0453]¹H-NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 2.69 (2H, d, J=6.8Hz),5.00-5.30 (3H, m), 6.91 (1H, br), 7.10-7.50 (7H, m), 7.54 (2H, m), 7.83(2H, d, J=8.0Hz), 8.09 (1H, d, J=8.0Hz), 8.61 (1H, d, J=8.0Hz), 12.40(1H, br)

Preparation 12-3

[0454] The following compound was prepared in a similar manner to thatof Preparation 6-3.

[0455](3RS)-3-benzyloxycarbonylamino-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[0456]¹H-NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 2.49-2.55 (1H, m),2.82-2.88 (1H, m), 5.10-5.20 (3H, m), 6.49 (1H, d, J=8.0Hz), 7.08 (1H,d, J=8.0Hz), 7.30-7.50 (6H, m), 7.46-7.50 (1H, m), 7.58 (1H, d,J=8.0Hz), 8.33 (1H, s)

Preparation 12-4

[0457] The following compound was prepared in a similar manner to thatof Preparation 1-5.

[0458](3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[0459]¹H-NMR (CDCl₃, δ): 0.80-1.80 (19H, m), 2.10 (2H, br), 2.51-2.57(1H, m), 2.82-2.88 (1H, m), 3.43-3.48 (1H, m), 3.56-3.60 (1H, m),3.67-3.72 (1H, m), 3.85-3.89 (1H, m),4.18 (1H, d, J=16Hz), 4.97 (1H, d,J=16Hz), 5.04-5.16 (2H, m), 6.65 (1H, d, J=8.0Hz), 7.2-7.6 (9H, m)

Preparation 12-5

[0460] To a solution of(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(0.396 g) in methanol (15 ml) was added Pearlman's catalyst (0.111 g).The mixture was stirred under H₂ atmosphere over night. The catalyst wasfiltered off by suction filtration on Celite®. The filtrate wasconcentrated in vacuo to give(3RS)-3-amino-1-[(3-azalicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(0.298 g), which was used in a following reaction step without furtherpurification.

[0461]¹H-NMR (CDCl₃, δ): 0.80-1.20 (4H, m), 1.4-1.9 (15H, m), 2.00-2.20(4H, br), 2.57-2.63 (1H, m), 2.78-2.83 (1H, m), 3.50-3.90 (4H, m), 4.13(1H, d, J=16H), 4.42 (1H, s), 5.05 (1H, d, J=16Hz), 7.22-7.30 (2H, m),7.43-7.51 (2H, m)

Preparation 13-1

[0462] 2-(2-Fluorobenzoyl)-6-methylaniline was prepared in a similarmanner to that of Preparation 50-1.

[0463] mp: 65.5-67.5° C.

[0464] IR (Nujol, cm⁻¹): 3470, 3350, 1610, 1580, 1551, 1375, 1320, 1280,1218, 1088, 1002, 956, 830, 752

[0465]¹H-NMR (CDCl₃, δ): 2.20 (3H, s), 6.38 (2H, br), 6.52 (1H, t,J=7.6Hz), 7.08-7.46 (6H, m)

[0466] APCI-MS (m/z): 230 (M⁺+1)

Preparation 13-2

[0467](3RS)-3-Benzyloxycarbonylamino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[0468] mp: 222.5-225° C.

[0469] IR (Nujol, cm⁻¹): 3200, 1715, 1690, 1608, 1530, 1374, 1051, 860,750

[0470]¹H-NMR (DMSO-d₆, δ): 2.40 (3H, s), 5.05 (1H, d, J=8.9Hz), 5.08(2H, s), 7.0-7.62 (12H, m), 8.43 (1H, d, J=8.9Hz), 10.28 (1H, s)

[0471] APCI-MS (m/z): 418 (M⁺+1)

Preparation 13-3

[0472] (3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1-(2-methoxylphenacyl)-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0473] IR (Nujol, cm⁻¹): 1710, 1660

[0474]¹H-NMR (DMSO-d₆, δ): 2.46 (3H, s), 3.94 (3H, s), 4.60 (1H, d,18.1Hz), 5.06 (2H, br, s), 5.24 (1H, d, J=8.6Hz), 5.44 (1H, d,J=18.1Hz), 6.9-7.8 (15H, m), 8.4-8.6 (1H, m)

[0475] Mass (APCI): 566 (M⁺+1)

Preparation 13-4

[0476](3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methoxyphenacyl)-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0477] IR (Nujol, cm⁻¹) 1675

[0478]¹H-NMR(CDCl₃, δ): 2.45 (3H, s), 3.93 (3H, s), 4.59 (7H, d,J=18.0Hz), 4.65 (1H, d, J=7.6Hz), 5.52 (1H, d, J=18.0Hz), 6.9-7.5 (9H,m), 7.7-8.0 (2H, m)

[0479] Mass (APCI): 432 (M⁺+1)

Preparation 14

[0480] To a solution of(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(1.9 g) in ethanol (40 ml) was added 1N-sodium hydroxide solution (7 ml)under stirring at ambient temperature. The mixture was stirred for 20minutes under the same conditions. After removal of the solvent waterwas added into the mixture, which was adjusted to pH 4 with a dilutedhydrochloric acid and extracted with ethyl acetate twice. The combinedextract was washed with water and dried over magnesium sulfate. Removalof the solvent gave(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-hydroxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-oneas an amorphous mass (1.68 g, 95.3%).

[0481]¹H-NMR (CDCl₃, δ): 1.4-1.75 (8H, m), 1.9-2.1 (2H, m), 2.36 (3H,s), 3.19-3.34 (2H, m), 3.55-3.89 (2H, m), 4.51 (2H, dd, J=15.8 Hz, 298.4Hz), 4.75 (2H, dd, J=14.7Hz, J=27.6Hz), 5.10 (2H, s), 5.41 (1H, d,J=8.8Hz), 6.54 (1H, d, J=8.8Hz), 7.25-7.47 (8H, m)

[0482] APCI-MS (m/z): 519 (M⁺+1)

Preparation 15-1

[0483](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-nitrophenacyl)-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0484] IR (Nujol, cm⁻¹) 1710, 1675

[0485]¹H-NMR (DMSO-d₆, δ): 2.43 (3H, s), 4.66 (1H, d, J=18.1Hz), 5.06(2H, m), 5.26 (1H, d, J=9.1Hz), 5.45 (1H, d, J=18.0Hz), 7.07 (1H, d,J=7.7Hz), 7.2-8.0 (14H, m), 8.0-8.2 (1H, m), 8.4-8.6 (1H, m)

[0486] Mass (APCI): 581 (M⁺+1)

Preparation 15-2

[0487](3RS)-3-Amino-1-(2-aminophenacyl)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0488] mp: 139.7-147.0° C.

[0489] IR (Nujol, cm⁻¹): 1680, 1660

[0490]¹H-NMR (DMSO-d₆, δ): 2.46 (3H, s), 4.10 (1H, s), 4.49 (1H, d,J=16.8Hz), 5.74 (1H, d, J=16.8Hz), 6.0 (2H, m), 6.5-6.7 (2H, m), 7.0-7.3(7H, m), 7.3-7.6 (2H, m), 7.6-7.7 (1H, m), 7.7-7.9 (1H, m)

[0491] Mass (APCI): 417 (M⁺+1)

Preparation 16-1

[0492] 2-Amino-3-methyl-2′-fluorobenzophenone was prepared in a similarmanner to that of Preparation 50-1.

[0493] mp: 52.2-55.2° C.

[0494] IR (Nujol, cm⁻¹) 3470, 3330. 1620

[0495]¹H-NMR (CDCl₃, δ): 2.21 (3H, s), 6.6-6.8 (3H, m), 7.0-7.7 (5H,m)

[0496] Mass (APCI): 230 (M⁺+1)

Preparation 16-2

[0497] 2-Bromoacetylamino-3-methyl-2′-fluorobenzophenone was prepared ina similar manner to that of Preparation 29-2.

[0498] mp: 100.1-103.2° C.

[0499] IR (Nujol, cm⁻¹): 1660

[0500]¹H-NMR (DMSO-d₆, δ): 2.26 (3H, s), 3.70 (2H, s), 7.2-7.4 (4H, m),7.4-7.8 (3H, m), 9.96 (1H, br, s)

[0501] Mass (APCI): 352 (M⁺+1), 350 (M⁺−1)

Preparalion 16-3

[0502]5-(2-Fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxidewas prepared in a similar manner to that of Preparation 19-3.

[0503] mp: 204.4-205.1° C.

[0504] IR (Nujol, cm⁻¹) 1690

[0505]¹H-NMR (CDCl₃, δ): 2.48 (3H, s), 4.70 (2H, s), 6.9-7.0 (1H, m),7.0-7.6 (6H, m), 9.31 (1H, br, s)

[0506] Mass (APCI m/z): 285 (M⁺+1)

Preparation 16-4

[0507]3-Acetoxy-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 19-4.

[0508] IR (Nujol, cm⁻¹): 1745

[0509]¹H-NMR (CDCl₃, δ): 2.32 (3H, s), 2.44 (3H, s), 5.97 (1H, s),7.0-7.2 (3H, m), 7.2-7.3 (1H, m), 7.3-7.5 (2H, m), 7.6-7.8 (1H, m), 8.62(1H, br, s)

[0510] Mass (APCI): 327 (M⁺+1)

Preparation 16-5

[0511](3RS)-3-Phthalimido-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 20-5.

[0512] mp: >250° C.

[0513] NMR (CDCl₃, δ): 2.44 (3H, s), 5.93 (1H, s), 6.9-8.0 (11 H, m)

[0514] Mass (APCI): 414 (M⁺+1)

Preparation 16-6

[0515](3RS)-3-Amino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 19-6.

[0516] mp: 102.2-112.2° C.

[0517] IR (Nujol, cm⁻¹): 1685

[0518]¹H-NMR (CDCl₃, δ): 2.42 (3H, s), 4.49 (1H, s), 7.0-7.8 (7H, m),8.64 (1H, m)

[0519] Mass (APCI): 284 (M⁺+1)

Preparation 16-7

[0520](3RS)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 20-7.

[0521] mp: 183.2-186.6° C.

[0522]¹H-NMR (CDCl₃, δ): 1.48 (9H, s), 2.41 (3H, s), 5.31 (1H, d,J=8.7Hz), 6.39 (1H, d, J=8.7Hz), 7.0-7.2 (3H, m), 7.2-7.3 (1H, m),7.3-7.6 (2H, m), 7.6-7.8 (1H, m), 8.26 (1H, br, s)

[0523] Mass (APCI): 384 (M⁺+1)

Preparation 16-8

[0524](3RS)-1-Ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0525]¹H-NMR (CDCl₃, δ): 1.46 (9H, s), 2.40 (3H, s), 3.91(1H, d,J=16.8Hz), 3.8-4.2 (2H, m), 4.83 (1H, d, J=16.8Hz), 5.40 (1H, d,J=8.9Hz), 6.41 (1H, d, J=8.8Hz), 7.0-7.4 (4H, m), 7.3-7.6 (2H, m),7.7-7.9 (1H, m)

[0526] Mass (APCI): 470 (M⁺+1)

Preparation 16-9

[0527](3RS)-1-Carboxymethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Example 48-2.

[0528] mp: 132.1-149.3° C.

[0529] IR (Nujol, cm⁻¹): 1700

[0530]¹H-NMR (CDCl₃, δ): 1.45 (9H, s), 2.36 (3H, s), 3.89 (1H, d,J=17.2Hz), 4.82 (1H, d, J=17.2Hz), 5.38 (1H, d, J=8.9Hz), 6.40 (1H, d,J=8.9Hz), 6.9-7.8 (7H, m)

[0531] Mass (APCI) : 442 (M⁺+1)

Preparation 16-10

[0532](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0533] mp: 108.1-113.9° C.

[0534]¹H-NMR (CDCl₃, δ): 1.45 (9H, s), 1.3-2.2 (10H, m), 2.45(3H, s),3.2-3.9 (4H, m), 4.04 (1H, d, J=15.5Hz), 5.05 (1H, d, J=15.5Hz), 5.42(1H, d, J=8.9Hz), 6.40 (1H, d, J=10Hz), 6.9-7.3 (4H, m), 7.3-7.5 (2H,m), 7.7-7.9 (1H, m)

[0535] Mass (APCI): 549 (M⁺+1)

Preparation 16-11

[0536](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 30-2.

[0537] mp: 102.3-113.4° C.

[0538]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.41 (3H, s), 3.0-3.4 (2H,m), 3.6-3.9 (2H, m), 4.06 (1H, d, J=16.2Hz), 4.36 (1H, s), 5.06 (1H, d,J=16.2Hz), 6.9-7.0 (1H, m), 7.1-7.4 (3H, m), 7.4-7.6 (2H, m), 7.6-7.8(1H, m)

[0539] Mass (APCI): 449 (M⁺+1)

Preparation 17-1

[0540] To a solution of o-toluidine (27.98 g) andcyclohexanecarbonitrile (14.25 g) in toluene (200 ml) was added dropwise1N-borontrichloride toluene solution (131 ml) under stirring and coolingin an ice-bath below 5° C. After the addition was completed, the mixturewas stirred at ambient temperature for 0.5 hour. The mixture was cooledagain and aluminum chloride (17.40 g) was added portionwise. The mixturewas gradually warmed to ambient temperature and then refluxed understirring for 7.5 hours. The reaction mixture was cooled in an ice-bathand 2N-hydrochloric acid (180 ml) was added dropwise under stirring. Theresultant mixture was refluxed again for 2.5 hours. The reaction mixturewas cooled under stirring and the resultant precipitate was filteredoff. The filtrate and washings with ethyl acetate were combined andextracted with ethyl acetate. The organic extract was washed with1N-hydrochloric acid twice and brine successively and dried overmagnesium sulfate. Removal of the solvent in vacuo gave an oil, whichwas subjected to column chromatography on silica gel eluting with amixture of n-hexane and methylene chloride (2:1). The fractionscontaining the desired product were combined and evaporated in vacuo togive 2-cyclohexylcarbonyl-6-methylaniline (27.9 g, 98.4% yield) as alight yellow oil.

[0541] IR (Film, cm⁻¹): 3470, 3320, 1638, 1608, 1580, 1550, 1424, 1380,1310, 1240, 1218, 1150, 1004, 980, 891, 740

[0542]¹H-NMR (CDCl₃, δ): 1.2-1.95 (8H, m), 2.16 (3H, s), 3.23-3.36 (1H,m), 6.4 (1H, br), 6.60 (1H, t, J=7.3Hz), 7.18 (1H, d, J=7.3Hz), 7.68(1H, d, J=7.3Hz)

[0543] APCI-MS (m/z): 218 (M⁺+1)

Preparation 17-2

[0544] To a solution of N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine(3.59 g) in dry tetrahydrofuran (THF, 30 ml) was added oxalyl chloride(1.05 ml) at 0-5° C. under stirring and nitrogen stream. After one dropof dimethylformamide was added, the mixture was stirred for 2 hoursunder the same conditions. To the reaction mixture was added dropwise amixture of 2-cyclohexycarbonyl-6-methylaniline (2.17 g) andN-methylmorpholine (2.23 g) in dry THF for 20 minutes under the sameconditions. The mixture was allowed to warm to ambient temperature andstirred for 1 hour. THF was removed in vacuo to afford a residue, whichwas dissolved in ethyl acetate and washed with diluted aqueous sodiumbicarbonate, water and brine successively. After drying over magnesiumsulfate, the solvent was removed in vacuo to give an amorphous mass(5.77 g), which was dissolved in methanol (4 ml). To the solution wasadded 9M methanolic ammonia (22 ml) and the mixture was stirred atambient temperature overnight. The mixture was evaporated in vacuo togive a residue, which was dissolved in ethyl acetate and washed with1N-sodium hydroxide aqueous solution and water. The organic layer wasdried over magnesium sulfate and evaporated in vacuo to give a residue,which was dissolved in acetic acid (60 ml). Ammonium acetate (4.0 g) wasadded to the solution and the mixture was stirred for 1.5 hour atambient temperature. Acetic acid was removed in vacuo to give a residue,which was dissolved in ethyl acetate and washed with diluted sodiumhydroxide aqueous solution and water successively. After drying overmagnesium sulfate, the solvent was removed in vacuo to give acrystalline mass, which was pulverized in a mixture of diisopropyl etherand n-hexane and collected by filtration to give(3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(2.36 g, 58.3% yield) as a crystalline powder.

[0545] mp: 171-173° C.

[0546] IR (Nujol, cm⁻¹): 3490 (sh), 3300, 3200, 1710, 1685, 1620, 1520,1370, 1056, 987, 793, 749, 696

[0547]¹H-NMR (DMSO-d₆, δ): 0.8-2.0 (8H, m), 2.33 (3H, s), 2.91 (1H, br,t), 4.86 (1H, d, J=8.7Hz), 5.03 (2H, s), 7.16-7.60 (8H, m), 8.11 (1H, d,J=8.7Hz), 9.96 (1H, s)

[0548] APCI-MS (m/z): 406 (M⁺+1)

Preparation 17-3

[0549](3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-1,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0550]¹H-NMR(CDCl₃, δ): 1.0-2.0 (8H, m), 2.34 (3H, s), 2.75-2.80 (1H,m), 3.16 (3H, s), 5.01-5.15 (2H, m), 5.18 (1H, d, J=8.5Hz), 6.54 (1H, d,J=8.4Hz), 7.2-7.4 (8H, m)

[0551] Mass (APCI): 420 (M⁺+1)

Preparation 17-4

[0552](3RS)-3-Amino-5-cyclohexyl-2,3-dihydro-1,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0553]¹H-NMR (CDCl₃, δ): 0.8-2.0 (10H, m), 2.34 (3H, s), 2.7-2.9 (1H,m), 3.16 (3H, s), 4.34 (1H, br, s), 7.1-7.5 (3H, m)

[0554] Mass (APCI): 286 (M⁺+1)

Preparation 18-1

[0555](3RS)-1-(2-methylphenacyl)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3. ¹H-NMR(CDCl₃, δ): 1.47 (9H, s), 2.35 (3H, s), 2.44 (3H, s), 4.36 (1H, d,J=17.2Hz), 5.49 (1H, d, J=17.2Hz), 5.51 (1H, d, J=7.3Hz), 6.42 (1H, d,J=8.9Hz), 7.0-7.5 (9H, m), 7.5-7.7 (1H, m), 7.8-8.0 (1H, m)

[0556] Mass (APCI): 516 (M⁺+1)

Preparation 18-2

[0557](3RS)-3-Amino-1-(2-methylphenacyl)-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 30-2.

[0558] mp: 198.1-202.6° C.

[0559] IR (Nujol, cm⁻¹): 1695, 1665

[0560]¹H-NMR (DMSO-d₆, δ): 2.26 (3H, s), 2.44 (3H, s), 4.44 (1H, s),4.60 (1H, d, J=17.4Hz), 5.40 (1H, d, J=17.4Hz), 7.0 (1H, m), 7.2-8.0(11H, m)

[0561] Mass (APCI): 416 (M⁺+1)

Preparation 19-1

[0562] 2-Amino-3-ethyl-2′-fluorobenzophenone was prepared in a similarmanner to that of Preparation 50-1.

[0563] IR (Neat, cm⁻¹): 1620

[0564]¹H-NMR (CDCl₃, δ): 1.30 (3H, t, J=7.5Hz), 2.55 (2H, q, J=7.5Hz),6.5-6.7 (3H, m), 7.0-7.7 (5H, m)

[0565] Mass (APCI): 244 (M⁺+1)

Preparation 19-2

[0566] 2-Bromoacetylamino-3-ethyl-2′-fluorobenzophenone was prepared ina similar manner to that of Preparation 29-2.

[0567] mp: 90.2-91.6° C.

[0568]¹H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7.5Hz), 2.69 (2H, q, J=7.5Hz),3.87 (2H, s), 7.0-7.4 (4H, m), 7.4-7.7 (3H, m), 9.02 (1H, br, s)

[0569] Mass (APCI): 366 (M⁺+2), 364 (M⁺)

Preparation 19-3

[0570] A mixture of 2-bromoacetylamino-3-ethyl-2′-fluorobenzophenone(12.0 g), hydroxylamine hydrochloride (17.65 g), sodium hydroxide (8.58g) in ethanol was stirred at 30-40° C. for 4.5 hours. Concentratedaqueous hydrochloric acid (14.8 ml) was added to the reaction mixture,which was stirred at room temperature overnight. The mixture wasevaporated in vacuo to afford precipitates. Water was added to theresultant mixture. The precipitate was collected by filtration andwashed with water to afford5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide(9.25 g, 94.2%).

[0571] mp: 170.9-176.2° C.

[0572]¹H-NMR (CDCl₃, δ): 1.30 (3H, t, J=7.4Hz), 2.82 (2H, q, J=7.4Hz),4.69 (2H, s), 6.8-7.0 (1H, m), 7.0-7.6 (6H, m), 9.05 (1H, br, s)

[0573] Mass (APCI): 299 (M⁺+1)

Preparation 19-4

[0574] A mixture of9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide(9.0 g) and acetic anhydride (32 ml) in chloroform (32 ml) was stirredat room temperature overnight. The reaction mixture was evaporated toremove chloroform. Diisopropyl ether was added to the residue to affordpowder, which was collected by filtration and washed with diisopropylether to give(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(6.30 g, 61.3%).

[0575] mp: 225.8-228.1° C.

[0576] IR (Nujol, cm⁻¹): 1730, 1680

[0577]¹H-NMR (DMSO-d₆, δ): 1.18 (3H, t, J=7.4Hz), 2.20 (3H, s), 2.6-2.8(1H, m), 2.8-3.1 (1H, m), 5.67 (1H, s), 7.0-7.8 (7H, m)

[0578] Mass (APCI): 341 (M⁺+1)

Preparation 19-5

[0579](3RS)-9-Ethyl-3-phthalimido-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 20-5.

[0580] IR (Nujol, cm⁻¹): 1710, 1670

[0581]¹H-NMR (DMSO-d₆, δ): 1.0-1.3 (3H, m), 2.6-2.9 (1H, m), 2.9-3.2(1H, m), 5.67 (1H, s), 7.0-7.1 (1H, m), 7.1-7.5 (3H, m), 7.5-7.8 (3H,m), 7.8-8.1 (4H, m)

[0582] Mass (APCI): 428 (M⁺+1)

Preparation 19-6

[0583] A mixture of(3RS)-3-phthalimido-9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one(6.0 g) and hydrazine hydrate (1.05 g) in a mixture of methanol andtetrahydrofuran (1:1, 60 ml) was refluxed with stirring for 3 hours. Thereaction mixture was allowed to cool to room temperature, and theresultant precipitates were filtered off. The filtrate and the washingswere combined and evaporated in vacuo to give a residue, which wasdissolved in ethyl acetate and washed with a saturated aqueous solutionof sodium bicarbonate, water and brine successively. The solvent wasdried over sodium sulfate and evaporated in vacuo to afford a paleyellow powder, which was washed with diisopropyl ether and collected byfiltration to give(3RS)-3-amino-9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one(3.37 g, 81.0%).

[0584] mp: 178.2-180.6° C.

[0585] IR (Nujol, cm⁻¹): 1620

[0586]¹H-NMR (DMSO-d₆, δ): 1.18 (3H, t, J=7.5Hz), 2.6-3.1 (2H, m), 4.22(1H, s), 7.0-7.7 (7H, m)

[0587] Mass (APCI): 298 (M⁺+1)

Preparation 19-7

[0588](3RS)-3-Tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 20-7.

[0589] mp: 88.1-92.1° C.

[0590] IR (Nujol, cm⁻¹) 1670, 1720

[0591]¹H-NMR(CDCl₃, δ): 1.2-1.4 (3H, m), 1.48 (9H, s), 2.6-2.9 (2H, m),5.31 (1H, d, J=8.6Hz), 6.40 (1H, d, J=8.6Hz), 7.0-7.4 (4H, m), 7.4-7.6(2H, m), 7.6-7.8 (1H, m), 8.16 (1H, br, s)

[0592] Mass (APCI): 398 (M⁺+1)

Preparation 19-8

[0593](3RS)-1-Ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0594] IR (Nujol, cm⁻¹): 1750, 1680

[0595]¹H-NMR (CDCl₃, δ): 1.33 (3H, t, J=6.0Hz), 0.99 (3H, t, J=7.1Hz),1.46 (3H, s), 2.6-2.8 (2H, m), 3.7-4.1 (3H, m), 4.88 (1H, d, J=16.6Hz),5.39 (1H, d, J=8.8Hz), 6.42 (1H, d, J=8.8Hz), 7.0-7.2 (2H, m), 7.2-7.4(2H, m), 7.4-7.6 (2H, m), 7.7-7.9 (1H, m)

[0596] Mass (APCI): 484 (M⁺+1)

Preparation 19-9

[0597](3RS)-1-Carboxymethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Example 48-2.

[0598] IR (Nujol, cm⁻¹):1720, 1680

[0599]¹H-NMR (CDCl₃, δ): 1.25 (3H, t, J=7.1Hz), 1.45 (9H, s), 2.6-2.8(2H, m), 3.85 (1H, d, J=17.2Hz), 4.87 (1H, d, J=17.2Hz), 5.37 (1H, d,J=8.8Hz), 6.40 (1H, d, J=8.8Hz), 7.0-7.9 (7H, m)

[0600] Mass (APCI): 456 (M⁺+1)

Preparation 19-10

[0601](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0602] IR (Nujol, cm⁻¹) 1720, 1650

[0603]¹H-NMR(CDCl₃, δ): 1.34 (3H, t, J=7.5Hz), 1.45 (9H, s), 1.4-2.2(10H, m), 2.7-2.9 (2H, m), 3.2-3.8 (4H, m), 3.96 (1H, d, J=15.5Hz), 5.01(1H, d, J=15.5Hz), 5.41 (1H, br, s), 7.0-7.1 (2H, m), 7.1-7.3 (2H, m),7.3-7.5 (2H, m), 7.7-7.9 (1H, m)

[0604] Mass (APCI): 563 (M⁺+1)

Preparation 19-11

[0605](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 30-2.

[0606] mp: 160.4-164.8° C.

[0607]¹H-NMR (DMSO-d₆, δ): 1.26 (3H, t, J=7.4Hz), 1.3-2.2 (10H, m), 2.75(2H, q, J=7.4Hz), 3.0-3.4 (2H, m), 3.4-3.9 (2H, m), 3.97 (1H, d,J=16.1Hz), 4.36 (1H, br, s), 5.13 (1H, d, J=16.1Hz), 6.8-7.0 (1H, m),7.2-7.4 (3H, m), 7.4-7.6 (2H, m), 7.6-7.8 (1H, m)

[0608] Mass (APCI) : 160.4-164.8° C.

Preparation 20-1

[0609] 2-Amino-3-isopropyl-2′-fluorobenzophenone was prepared in asimilar manner to that of Preparation 50-1.

[0610] IR (Neat, cm⁻¹): 1620

[0611]¹H-NMR (CDCl₃, δ): 1.26 (3H, d, J=6.8Hz), 1.30 (3H, d, J=6.8Hz),2.7-3.1 (1H, m), 3.64 (1H, br), 6.5-7.6 (7H, m)

[0612] Mass (APCI): 258 (M⁺+1)

Preparation 20-2

[0613] 2-Bromoacetylamino-3-isopropyl-2-fluorobenzophenone was preparedin a similar manner to that of Preparation 29-2.

[0614] mp: 125.8-126.3° C.

[0615] IR (Nujol, cm⁻¹): 1660

[0616]¹H-NMR (CDCl₃, δ): 1.27 (6H, d, J=6.8Hz), 3.0-3.3 (1H, m), 3.86(2H, s), 7.0-7.4 (4H, m), 7.4-7.8 (3H, m), 8.86 (1H, s)

[0617] Mass (APCI): 380 (M⁺+2), 378 (M⁺)

Preparation 20-3

[0618] 5-(2-Fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide was prepared in a similar manner tothat of Preparation 19-3.

[0619] mp: 205.5-207.7° C.

[0620]¹H-NMR (CDCl₃, δ): 1.32 (6H, d, J=6.7Hz), 3.2-3.4 (1H, m), 4.70(2H, s), 6.8-7.0 (1H, m), 7.0-7.3 (3H, m), 7.3-7.5 (3H, m), 8.91 (1H,br, s)

[0621] Mass (APCI): 313 (M⁺+1)

Preparation 20-4

[0622](3RS)-3-acetoxy-5-(2-fluoropheyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 19-4.

[0623] mp: 243.2-247.1° C.

[0624]¹H-NMR (DMSO-d₆, δ): 1.12 (3H, d, J=6.7Hz), 1.31 (1H, d, J=8.0Hz),2.20 (3H, s), 3.3-3.6 (1H, m), 5.65 (1H, s), 7.0-7.1 (1H, m), 7.1-7.5(3H, m), 7.5-7.7 (3H, m), 10.40 (1H, br, s)

[0625] Mass (APCI): 355 (M⁺+1)

Preparation 20-5

[0626] A mixture of(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(2.73 g), sodium iodide (11.5 g) and phthalimide potassium salt (2.14 g)in N,N-dimethylformamide (18 ml) was stirred at 90° C. for 1.3 hours.The hot reaction mixture was poured into an ice with stirring to affordprecipitates, which were collected by filtration, washed with water andair dried at room temperature to afford(3RS)-3-phthalimido-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(3.08 g, 90.6%) as a crystalline powder.

[0627] mp: 247.6-252.2° C.

[0628] IR (Nujol, cm⁻¹): 1680

[0629]¹H-NMR (DMSO-d₆, δ): 1.12 (3H, d, J=6.7Hz), 1.33 (3H, d, J=6.6Hz),3.3-3.7 (1H, m), 5.65 (1H, s), 7.0-7.2 (1H, m), 7.2-7.5 (3H, m), 7.5-7.8(3H, m), 7.8-8.1 (4H, m)

[0630] Mass (APCI): 442 (M⁺+1)

Preparation 20-6

[0631](3RS)-3-Amino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 19-6.

[0632] mp: 192.3-198.6° C.

[0633] IR (Nujol, cm⁻¹): 1690

[0634]¹H-NMR (DMSO-d₆, δ): 1.11 (3H, d, J=6.7Hz), 1.29 (1H, d, J=6.7Hz),3.3-3.6 (1H, m), 4.20 (1H, s), 6.9-7.7 (7H, m)

[0635] Mass (APCI): 312 (M⁺+1)

Preparation 20-7

[0636] A mixture of(3RS)-3-amino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(1.5g), a catalytic amount of hydroxylamine hydrochloride, triethylamine(731 mg) and di-tert-butyl dicarbonate (1.57 g) in methylene chloride(30 ml) was stirred at room temperature for 1.5 hours. Chloroform andwater were added to the reaction mixture. The separated organic layerwas washed with water twice and dried over magnesium sulfate. Thesolvent was evaporated in vacuo to afford a crude paste, which wasdissolved in diisopropyl ether, and allowed to stand at room temperatureto afford a pale yellow powder. The powder was collected by filtrationand washed with diisopropyl ether to afford(3RS)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(1.55 g, 78.1%).

[0637] mp: 196.0-199.2° C.

[0638] IR (Nujol, cm⁻¹): 1715, 1665

[0639]¹H-NMR (CDCl₃, δ): 1.32 (3H, t, J=6.6Hz), 1.48 (9H, s), 3.1-3.3(1H, m), 5.32 (1H, d, J=8.6Hz), 6.41 (1H, d, J=8.6Hz), 7.0-7.4 (4H, m),7.4-7.6 (2H, m), 7.6-7.8 (1H, m), 8.15 (1H, br, s)

[0640] Mass (APCI): 412 (M⁺+1)

Preparation 20-8

[0641](3RS)-1-Ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0642] IR (Nujol, cm⁻¹): 1750, 1720, 1670

[0643]¹H-NMR (CDCl₃, δ): 0.99 (1H, t, J=7.1Hz), 1.20 (3H, d, J=6.7Hz),1.4-1.6 (3H, m), 1.46 (9H, s), 3.7-4.2 (3H, m), 3.0-3.2 (1H, m), 4.94(1H, d, J=16.5Hz), 5.39 (1H, d, J=8.7Hz), 6.41 (1H, d, J=8.7Hz), 7.0-7.2(2H, m), 7.2-7.4 (2H, m), 7.4-7.6 (2H, m), 7.7-7.9 (1H, m)

[0644] Mass (APCI): 498 (M⁺+1)

Preparation 20-9

[0645](3RS)-1-Carboxymethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Example 48-2.

[0646] IR (Nujol, cm⁻¹): 1720, 1690

[0647]¹H-NMR (CDCI₃, δ): 1.14 (3H, d, J=7.6Hz), 1.39 (3H, d, J=6.8Hz),1.45 (9H, s), 2.9-3.1 (1H, m), 3.81 (1H, d, J=17.1Hz), 4.95 (1H, d,J=17.1Hz), 5.37 (1H, d, J=8.8Hz), 6.39 (1H, d, J=8.8Hz), 7.0-7.6 (6H,m), 7.6-7.8 (1H, m)

[0648] Mass (APCI): 470 (M⁺+1)

Preparation 20-10

[0649](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0650] IR (Nujol, cm⁻¹): 1720, 1650

[0651]¹H-NMR (CDCl₃, δ): 1.21 (3H, d, J=6.6Hz), 1.41 (3H, d, J=6.6Hz),1.45 (9H, s), 1.4-2.2 (10H, m), 3.1-3.42 (2H, m), 3.42-3.6 (1H, m),3.7-3.9 (1H, m), 3.92 (1H, d, J=15.4Hz), 5.16 (1H, d, J=15.4Hz), 5.41(1H, d, J=8.9Hz), 6.39 (1H, d, J=8.9Hz), 7.0-7.2 (2H, m), 7.2-7.35 (2H,m), 7.35-7.6 (2H, m), 7.7-7.9 (1H, m)

[0652] Mass (APCI): 577 (M⁺+1)

Preparation 20-11

[0653](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-9-isopropyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 30-2.

[0654] mp: 211.6-214.2° C.

[0655] IR (Nujol, cm⁻¹): 1080, 1640

[0656]¹H-NMR (DMSO-d₆, δ): 1.10 (3H, d, J=6.6Hz), 1.38 (1H, d, J=6.6Hz),1.4-2.2 (10H, m), 3.0-3.4 (2H, m), 3.6-3.8 (2H, m), 3.84 (1H, d,J=16.3Hz), 4.36 (1H, br, s), 5.22 (1H, d, J=16.3Hz), 6.8-7.0 (1H, m),7.2-7.4 (3H, m), 7.4-7.8 (3H, m)

[0657] Mass (APCI): 477 (M⁺+1)

Preparation 21-1

[0658](3RS)-1-(2-Acetoxyethyl)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0659] IR (Nujol, cm⁻¹) 1720, 1675, 1610

[0660]¹H-NMR(CDCl₃, δ): 1.2-2.2 (10H, m), 2.32 (3H, s), 2.84 (1H, m),3.39 (1H, d, t, J=6.0Hz and J=14.2Hz), 3.9-4.0 (2H, m), 4.60 (1H, d, t,J=5.4Hz and J=14.2Hz), 5.0-5.2 (3H, m), 6.53 (1H, d, J=8.5Hz), 7.2-7.5(8H, m)

[0661] Mass (APCI): 492 (M⁺+1)

Preparation 21-2

[0662](3RS)-3-Amino-1-(2-acetoxyethyl)-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0663]¹H-NMR (CDCl₃, δ): 1.2-2.2 (10H, m), 2.33 (3H, s), 2.7-2.9 (1H,m), 3.3-3.5 (1H, m), 3.8-4.1 (2H, m), 4.29 (1H, br, s), 4.61 (1H, dt,J=5.3Hz and J=14.1Hz), 7.2-7.5 (3H, m)

[0664] Mass (APCI): 358 (M⁺+1)

Preparation 22

[0665] A mixture of(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(1.0 g) and 1,1′-carbonyldiimidazole (723 mg) in tetrahydrofuran (20 ml)was stirred at room temperature overnight. Ethyl acetate and water wereadded to the reaction mixture. The separated organic layer was washedwith water twice, brine and dried over magnesium sulfate. The solventwas evaporated in vacuo to afford(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-3-(imidazol-1-yl)carbonylamino-1H-1,4-benzodiazepin-2-one(1.27 g) as a crystalline powder.

[0666] mp: 107.3-118.2° C.

[0667] IR (Nujol, cm⁻¹): 1680, 1645 ¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H,m), 2.45 (3H, s), 2.9-3.4 (2H, m), 3.7-4.0 (2H, m), 4.12 (1H, d,J=16.0Hz), 5.18 (1H, d, J=16.0Hz), 5.48 (1H, d, J=7.4Hz), 6.9-7.1 (2H,br, m), 7.2-7.4 (2H, m), 7.5-7.7 (2H, m), 7.7-7.8 (1H, m), 7.91 (1H, br,s), 8.43 (1H, br, s), 9.84 (1H, d, J=7.4Hz)

[0668] Mass (APCI): 475 (M⁺+1)

Preparation 23-1

[0669](3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-1-ethoxycarbonyl-methyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0670] IR (Nujol, cm⁻¹): 1750, 1720, 1670

[0671]¹H-NMR (CDCl₃, δ): 1.1-2.2 (10H, m), 1.21 (3H, t, J=7.1Hz), 2.33(3H, s), 2.7-2.9 (1H, m), 3.82 (1H, d, J=16.7Hz), 4.12 (2H, q, J=7.1Hz),4.68 (1H, d, J=16.7Hz), 5.0-5.2 (2H, br, m), 5.22 (1H, d, J=8.6Hz), 6.47(1H, d, J=8.6Hz), 7.1-7.5 (8H, m)

[0672] Mass (APCI): 492 (M⁺+1)

Preparation 23-2

[0673](3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-1-carboxymethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Example 48-2.

[0674] IR (Nujol, cm⁻¹): 1720, 1680

[0675]¹H-NMR (CDCl₃, δ) : 1.1-2.2 (10H, m), 2.33 (3H, s), 2.81 (1H, m),3.84 (1H, d, J=17.1Hz), 4.72 (1H, d, J=17.1Hz), 4.9-5.2 (2H, br, m),5.21 (1H, d, J=8.6Hz), 6.52 (1H, d, J=8.7Hz), 7.2-7.5 (8H, m)

[0676] Mass (APCI): 464 (M⁺+1)

Preparation 23-3

[0677](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0678] IR (Nujol, cm⁻¹): 1720, 1660

[0679]¹H-NMR (CDCl₃, δ): 1.1-2.2 (20H, m), 2.35 (3H, s), 2.7-3.0 (1H,m), 3.3-3.9 (4H, m), 3.88 (1H, d, J=15.5Hz), 4.96 (1H, d, J=15.5Hz),4.9-5.2 (2H, m), 5.23 (1H, d, J=8.6Hz), 6.50 (1H, d, J=8.7Hz), 7.2-7.6(8H, m)

[0680] Mass (APCI): 571 (M⁺+1)

Preparation 23-4

[0681](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-³-yl)carbonylmethyl]-5-cyclohexyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 49-2.

[0682] IR (Nujol, cm⁻¹): 1660

[0683]¹H-NMR (CDCl₃, δ): 1.1-2.2 (10H, m), 2.41 (3H, s), 2.7-3.0 (1H,br, s), 3.3-3.8 (4H, m), 3.91 (1H, d, J=15.8Hz), 5.09 (1H, d, J=5.2Hz),5.14 (1H, d, J=15.8Hz), 7.2-7.5 (3H, m)

[0684] Mass (APCI): 437 (M⁺+1)

Preparation 24-1

[0685](3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-9-methyl-1-(2-methylphenacyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0686] IR (Nujol, cm⁻¹): 1720, 1660

[0687]¹H-NMR(CDCl₃, δ): 1.1-2.2 (10H, m), 2.35 (3H, s), 2.38 (3H, s),2.8-3.0 (1H, m), 4.22 (1H, d, J=17.0Hz), 5.0-5.2 (2H, br, m), 5.28 (1H,d, J=8.7Hz), 5.40 (1H, d, J=17.0Hz), 6.51 (1H, d, J=8.6Hz), 7.2-7.6(11H, m), 7.6-7.7 (1H, m)

[0688] Mass (APCI): 538 (M⁺+1)

Preparation 24-2

[0689](3RS)-3-Amino-5-cyclohexyl-2,3-dihydro-9-methyl-1-(2-methylphenacyl)-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 49-2.

[0690] IR (Nujol, cm⁻¹): 1680

[0691]¹H-NMR (CDCl₃, δ): 1.2-2.3 (10H, m), 2.38 (3H, s). 2.39 (3H, s),2.85 (1H, m), 4.22 (1H, d, J=17.1Hz), 4.66 (1H, br, s), 5.45 (1H, d,J=17.1Hz), 7.2-7.5 (6H, m), 7.5-7.7 (1H, m)

[0692] Mass (APCI): 404 (M⁺+1)

Preparation 25-1

[0693] To a solution of 2-chloroacetyl-6-methylaniline (1.84 g) inmethanol (50 ml) was added a 15% aqueous solution of sodiummethanthiolate (14.01 g, 3 eq.mol) under stirring and cooling in anice-bath. The mixture was stirred at ambient temperature for 2.5 hours.From the reaction mixture methanol was removed in vacuo and dissolved inethyl acetate. The solution was washed with water and brine successivelyand dried over magnesium sulfate. Removal of the solvent in vacuo gavean oil (2.26 g), which was subjected to column chromatography on silicagel eluting with a mixture of n-hexane and chloroform (10:1). Thefractions containing the desired product were combined and evaporated togive 2-methylthioacetyl-6-methylaniline (1.75 g, 89.7%) as an oil.

[0694] IR (Film, cm⁻¹): 3470, 3340, 1635, 1610, 1583, 1555, 1459, 1430,1380, 1310, 1281, 1250, 1218, 1127, 1030, 980, 740

[0695]¹H-NMR (CDCl₃, δ): 2.18 (6H, s), 3.80 (2H, s), 6.35 (1H, br), 6.59(1H, t, J=7.2Hz), 7.21 (1H, d, J=7.2Hz), 7.62 (1H, d, J=7.2Hz)

[0696] APCI-MS (m/z): 196 (M⁺+1)

Preparation 25-2

[0697](3RS)-3-Benzyloxycarbonylamino-5-methylthiomethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[0698] mp: 152.6-153.8° C.

[0699] IR (Nujol, cm⁻¹): 3250 (sh), 3200, 1720, 1695, 1680 (sh), 1460,1375, 1059, 762, 700

[0700]¹H-NMR (CDCl₃, δ): 2.01 (3H, s), 2.37 (3H, s), 3.72 (2H, dd,J=13.7Hz, J=44.6Hz), 5.11 (2H, dd, J=12.3Hz, J=14.3Hz), 5.20 (1H, d,J=8.2Hz), 6.54 (1H, d, J=8.2Hz), 7.16-7.59 (8H, m), 7.98 (1H, s)

[0701] APCI-MS (m/z): 384 (M⁺+1)

Preparation 25-3

[0702](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl-9-methyl-5-methylthiomethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0703]¹H-NMR (CDCl₃, δ): 1.1-1.3 (3H, m), 2.18 (3H, s), 2.35 (3H, s),3.6-4.0 (2H, m), 4.08 (2H, q, J=7.1Hz), 4.71 (1H, d, J=16.9Hz), 5.0-5.2(2H, br, m), 5.30 (1H, d, J=8.6Hz), 6.55 (1H, d, J=8.5Hz), 7.2-7.5 (7H,m), 7.74 (1H, d, J=7.5Hz)

[0704] Mass (APCI): 470 (M⁺+1)

Preparation 25-4

[0705](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-9-methyl-5-methylthiomethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-4.

[0706]¹H-NMR (CDCl₃, δ): 2.0-2.2 (3H, m), 2.2-2.4 (3H, m), 3.6-4.0 (2H,m), 4.6-5.0 (1H, br), 5.6-5.2 (3H, m), 5.28 (1H, d, J=8.4Hz), 7.2-7.6(7H, m), 7.75 (1H, d, J=6.7Hz)

[0707] Mass (APCI): 442 (M⁺+1)

Preparation 25-5

[0708](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-9-methyl-5-methylthiomethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0709] IR (Nujol, cm⁻¹): 1725, 1675, 1640

[0710]¹H-NMR (CDCl₃, δ): 1.5-1.9 (8H, br), 1.9-2.1 (2H, br), 2.30 (3H,s), 2.36 (3H, s), 3.2-3.4 (2H, m), 3.5-3.7 (1H, m), 3.7-3.9 (4H, m),5.02 (1H, d, J=14.7Hz), 5.09 (2H, m), 5.32 (1H, d, J=8.5Hz), 6.54 (1H,d, J=8.5Hz), 7.2-7.5 (7H, m), 7.76 (1H, d, J=6.5Hz)

[0711] Mass (APCI): 549 (M⁺+1)

Preparation 26-1

[0712](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-[[(S)-N-(tert-butoxycarbonyl)phenylalanyl]amino]-5-(2-fluolophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0713]¹H-NMR (CDCl₃, δ): 1.38 (18H, s), 1.4-2.2 (20H, m), 2.44 (6H, s),3.1-3.6 (8H, m), 3.6-4.1 (4H, m), 4.56 (2H, m), 4.9-5.2 (4H, m), 5.62(1H, d, J=8.2Hz), 5.64 (1H, d, J=8.1Hz), 7.0-7.5 (16H, m), 7.5-7.9 (4H,m)

[0714] Mass(FAB): 696(M⁺+1)

Preparation 26-2

[0715] A mixture of(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-3-[[(S)-N-(tert-butoxycarbonyl)phenylalanyl]amino]-5-(2-fluolophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(900 mg) and 4N-hydrochloric acid in ethyl acetate (6 ml) was stirred atambient temperature for 1.5 hours. Ethyl acetate and saturated aqueoussodium bicarbonate were added to the reaction mixture at 0° C. Theseparated organic layer was washed with brine and dried over sodiumsulfate. The solvent was evaporated in vacuo to afford a crude whiteamorphous powder (672 mg) composing two diastereoisomers, which wereseparated by high-pressure liquid chromatography.

[0716] Each fraction containing the respective diastereoisomers wasevaporated in vacuo and dissolved in ethyl acetate. Each solution waswashed with aqueous sodium hydrogen carbonate respectively. Therespective separated organic layer was dried over sodium sulfate andevaporated in vacuo to afford each diastereoisomer of (3R)-and(3S)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-[(S)-phenylalanylamino]-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onerespectively. (S)-isomer: 257 mg, 33.4% yield. and (R)-isomer: 251 mg,32.7% yield.

[0717] (S)-isomer

[0718] Mass (APCI): 596 (M⁺+1)

[0719]¹H-NMR (CDCl₃,δ): 1.3-2.2 (10H, m), 2.45 (3H, s), 2.78 (1H, dd,J=9.1Hz and 13.7Hz), 3.2-3.6 (4H, m), 3.6-3.9 (2H, m), 4.01 (1H, d,J=15.5Hz), 5.10 (1H, d, J=15.5Hz), 5.68 (1H, d, J=8.6Hz), 7.0-7.6 (11H,m), 7.7-7.9 (1H, m), 8.92 (1H, d, J=8.6Hz)

[0720] (R)-isomer

[0721]¹H-NMR (CDCl₃, δ): 1.4-2.2 (10H, m), 2.46 (3H, s), 2.66 (1H, dd,J=10.4Hz and 13.7Hz), 3.3-3.6 (4H, m), 3.6-3.9 (2H, m), 4.03 (1H, d,J=15.5Hz), 5.11 (1H, d, J=15.5Hz), 5.67 (1H, d, J=8.5Hz), 7.0-7.6 (11H,m), 7.7-7.9 (1H, m), 8.91 (1H, d, J=8.4Hz)

[0722] Mass (APCI): 596 (M⁺+1)

Preparation 26-3

[0723] A mixture of(3S)-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-3-[(S)-phenylalanylamino]-5-(2-fluolophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(235 mg) and triethylamine (42 mg) in tetrahydrofuran (2.0 ml) wasstirred at room temperature. Phenylisothioisocyanate (109 mg) was addeddropwise to the reaction mixture, stirred for 30 minutes. The mixturewas evaporated in vacuo to dryness. A mixture of the residue andtrifluoroacetic acid (1.0 ml) was stirred at 50° C. for 45 minutes. Themixture was evaporated in vacuo to afford an oily residue. The oilyresidue was separated by column chromatography on silica gel to affordeither of (3R) or(3S)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onetrifluoroacetate (165 mg, 74.4% yield).

[0724]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.9-3.1 (1H,m), 3.1-3.4 (1H, m), 3.6-4.0 (2H, m), 4.18 (2H, d, J=16.2Hz), 5.17 (1H,d, J=16.2Hz), 5.21 (1H, br, s), 7.0-7.1 (1H, m), 7.2-7.5 (3H, m),7.5-7.8 (3H, m), 8.98 (2H, m)

[0725] Mass (APCI): 449 (M⁺+1)

Preparation 27

[0726](3R)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onetrifluoroacetate was prepared in a similar manner to that of Preparation26-3.

[0727]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.9-3.1 (1H,m), 3.1-3.4 (1H, m), 3.6-4.0 (4H, m), 4.18 (1H, d, J=16.3Hz), 5.17 (1H,d, J=16.3Hz), 5.21 (1H, br, s), 7.0-7.1 (1H, m), 7.2-7.5 (3H, m),7.5-7.8 (3H, m), 8.98 (2H, m)

[0728] Mass (APCI): 449 (M⁺+1)

Preparation 28-1

[0729](3RS)-2,3-Dihydro-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-methyl-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0730] IR (Nujol, cm⁻¹) 1720, 1680

[0731]¹H-NMR (CDCl₃, δ): 1.47 (9H, s), 2.52 (3H, s), 4.53 (1H, d,J=15.1Hz), 5.37 (1H, d, J=8.7Hz), 5.71 (1H, d, J=15.1Hz), 6.45 (1H, d,J=8.6Hz), 6.9-7.5 (9H, m), 7.5-7.7 (1H, m), 8.2-8.3 (1H, m)

[0732] Mass (APCI): 475 (M⁺+1)

Preparation 28-2

[0733](3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 30-2.

[0734] IR (Nujol, cm⁻¹): 1670

[0735]¹H-NMR (CDCl₃, δ): 2.52 (3H, s), 4.50 (1H, d, J=15.0Hz), 4.60 (1H,s), 5.73 (1H, d, J=15.0Hz), 7.0-7.7 (10H, m), 8.2-8.4 (1H, m)

[0736] Mass (APCI): 375 (M⁺+1)

Preparation 29-1

[0737] 2-Chloro-6-(2-fluorobenzoyl)aniline was prepared in a similarmanner to that of Preparation 50-1.

[0738] mp: 86-87.5° C.

[0739] IR (Nujol, cm⁻¹) 3400, 3290, 1620, 1600

[0740]¹H-NMR (CDCl₃, δ): 6.54 (1H, t, J=7.8Hz), 6.8-7.0 (2H, br),7.0-7.4 (3H, br. m), 7.4-7.6 (3H, br, m)

[0741] Mass (APCI): 250 (M⁺+1)

Preparation 29-2

[0742] To a solution of 2-amino-3-chloro-2′-fluorobenzophenone (4.80 g)and pyridine (3.04 g) in methylene chloride (100 ml) was added dropwisebromoacetyl bromide (3.42 ml) under stirring and cooling in an ice-bath.After the addition was completed, the mixture was stirred at ambienttemperature for 0.5 hour and refluxed for 0.5 hour. The mixture wasallowed to stand to cool to ambient temperature and evaporated in vacuoto give a residue, which was dissolved in ethyl acetate and washed withwater three times and brine successively. After drying over magnesiumsulfate and treating with active carbon, the solvent was removed invacuo to give a crystalline mass. Pulverization in diisopropyl ether andcollection by filtration afforded2-(bromoacetylamino)-3-chloro-2′-fluorobenzophenone (5.86 g, 82.4%yield) as a white crystalline powder.

[0743] IR (Nujol, cm⁻¹): 3270, 1679 (sh), 1670, 1608, 1594, 1512, 1375,1304, 1138, 1100, 975, 945, 826, 775, 752, 694

[0744]¹H-NMR (CDCl₃, δ) :3.83 (2H, s), 7.08-7.81 (7H, m), 8.84 (1H, s)

[0745] APCI-MS (m/z): 371 (M⁺+1)

Preparation 29-3

[0746] Sodium hydroxide (pellet, 2.82 g) was dissolved in a mixture ofmethanol (15 ml) and water (25 ml) under stirring. To the mixture wasadded hydroxylamine hydrochloride (5.50 g). To the clear solutionprepared above was portionwise added a suspension of2-bromoacetylamino-3-chloro-2′-fluorobenzophenone (5.80 g) in methanol(30 ml) under stirring at 30-35° C. After the addition was completed,the mixture was refluxed under stirring for 3 hours. Methanol wasremoved in vacuo and the residual mixture was extracted with ethylacetate. The extract was washed with water three times and dried overmagnesium sulfate. The solvent was removed in vacuo to afford an oil(5.0 g), which was pulverized in a mixture of diisopropyl ether andethyl acetate. The resultant crystalline mass was collected byfiltration and dried to give9-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-4-oxide(1.74 g, 36.5% yield) as a white crystalline powder.

[0747] IR (Nujol, cm⁻¹): 3350, 1700, 1610, 1490 (sh), 1478, 1350, 1298,1265, 1230, 1200, 1154, 1100, 992, 860, 819, 792, 750, 730

[0748]¹H-NMR (DMSO-d₆, δ): 4.66 (2H, br, s), 6.9-7.7 (7H, m), 10.73 (1H,s)

[0749] APCI-MS (m/z): 305 (M⁺+1), 307 (M⁺+3)

Preparation 29-4

[0750] A suspension of9-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-4-oxide(1.475 g) in acetic anhydride (12 ml) was refluxed for 0.5 hour. Theresultant clear solution was cooled in an ice-bath to affordprecipitate. To the cooled suspension was added diisopropyl ether (20ml) and the mixture was cooled further. The resultant precipitate wascollected by filtration and washed with diisopropyl ether to give(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one(0.84 g, 50.0% yield) as a colorless crystalline powder.

[0751] IR (Nujol, cm⁻¹): 3200, 3125, 1736, 1688, 1610, 1593, 1484, 1371,1322, 1212, 1091, 1060, 926, 794, 770, 748, 705

[0752]¹H-NMR (DMSO-d₆, δ): 2.21 (3H, s), 5.79 (1H, s), 7.18-7.83 (7H,m), 10.72 (1H, s)

[0753] APCI-MS (m/z): 347 (M⁺+1), 349 (M⁺+3)

Preparation 29-5

[0754] A mixture of(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one(3.60 g), sodium iodide (15.59 g) and potassium phthalimide (2.89 g,) indimethylformamide (25 ml) was stirred at 100° C. for 1 hour. Thereaction mixture was poured into ice-water and the resultant precipitatewas collected by filtration. After washing with water several times anddried over phosphorus pentoxide under reduced pressure, the crude powderwas subjected to column chromatography on silica gel eluting with amixture of chloroform and methanol (100:1). The fractions containing thedesired product were combined and evaporated in vacuo to give(3RS)-3-phthalimido-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one(0.82 g, 18.9% yield) as a crystalline powder.

[0755] IR (Nujol, cm⁻¹): 3350, 1780, 1720, 1710, 1380, 1125, 886, 746,712

[0756]¹H-NMR (DMSO-d₆, δ): 5.77 (1H, s), 7.20-8.02 (11H, m), 10.70 (1H,s)

[0757] APCI-MS (m/z): 434 (M⁺+1), 436 (M⁺+3)

Preparation 29-6

[0758] To a suspension of(3RS)-3-phthalimido-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one(0.8 g) in a mixed solvent of tetrahydrofuran and methanol (1:1, 8 ml)was added hydrazine hydrate (0.11 ml) under stirring at ambienttemperature. The mixture was stirred at ambient temperature for 0.5 hourand refluxed for 0.5 hours. After allowing to cool to ambienttemperature, the resultant precipitate was filtered off and washed withcold methanol. The filtrate and the washings were combined andevaporated in vacuo to afford a residue, which was subjected to columnchromatography on silica gel eluting with a mixture of chloroform andmethanol (50:1). The fractions containing the desired product werecombined and evaporated in vacuo to give a crystalline mass, which waspulverized in diisopropyl ether and collected by filtration to give(3RS)-3-amino-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one(0.54 g, 96.6% yield).

[0759] IR (Nujol, cm⁻¹): 3350, 3300, 1686, 1608, 1484, 1374, 1320, 1215,1130, 1018, 968, 830, 746, 715

[0760]¹H-NMR (CDCl₃, δ): 2.27 (2H, br, s), 4.50(1H, s), 7.03-7.68 (7H,m), 8.04 (1H, br, s)

[0761] APCI-MS (m/z): 304 (M⁺+1), 306 (M⁺+3)

Preparation 29-7

[0762] To a suspension of(3RS)-3-amino-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one(538.8 mg), triethylamine (269.2 mg) and a catalytic amount ofhydroxylamine hydrochloride in methylene chloride was added dropwise asolution of di-t-butyl dicarbonate (580.5 g) in methylene chloride (1ml) at ambient temperature under stirring. After the mixture was stirredfor 3.5 hours under the same conditions, triethylamine (89.7 mg) anddi-t-butyl dicarbonate (193.0 mg) was added. The mixture was stirredovernight at ambient temperature. Methylene chloride was removed invacuo to afford a residue, which was dissolved in ethyl acetate andwashed with water twice. After drying over magnesium sulfate, thesolvent was removed in vacuo to give an oil (1.10 g), which wassubjected to column chromatography on silica gel eluting withchloroform. Fractions containing the desired product were combined andevaporated in vacuo to give(3RS)-9-chloro-5-(2-fluorophenyl)-3-t-butoxycarbonylamino-2,3-dihydro-1H-1,4-benzodiazepin-2-one(566.1 mg, 79.2% yield) as a white crystalline powder.

[0763] mp: 187.1-188.6° C.

[0764] IR (Nujol, cm⁻¹): 3210, 3150 (sh), 1700 (sh), 1689, 1604, 1532,1365, 1327, 1270, 1254, 1170, 1059, 1020, 957, 945, 880, 834, 763, 746,680

[0765]¹H-NMR (DMSO-d₆, δ): 1.32 (2H, br, s), 1.41(9H, s), 5.03(1H, d,J=8.6Hz), 7.17-7.82 (7H, m), 7.91 (1H, d, J=8.6Hz), 10.56 (1H, s)

[0766] APCI-MS (m/z): 404 (M⁺+1), 406 (M⁺+3)

Preparation 29-8

[0767] (3 RS) -9 -Chloro-2,3-dihydro-3-tert-butoxycarbonylamino-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to that ofPreparation 59-3.

[0768] IR (Nujol, cm⁻¹): 1680

[0769]¹H-NMR (CDCl₃, δ): 1.00 (3H, t, J=7.1Hz), 1.46 (9H, s), 3.8-4.2(2H, m), 4.25 (1H, d, J=17.2Hz), 4.95 (1H, d, J=17.2Hz), 5.39 (1H, d,J=8.8Hz), 6.42 (1H, d, J=8.7Hz), 7.0-7.2 (1H, br, s), 7.2-7.4 (3H, m),7.4-7.6 (1H, br, s), 7.6-7.7 (1H, m), 7.7-7.9 (1H, m)

[0770] Mass (APCI): 490 (M⁺+1)

Preparation 29-9

[0771](3RS)-9-Chloro-2,3-dihydro-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-1-carboxymethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Example 48-2.

[0772] IR (Nujol, cm⁻¹): 1745, 1675

[0773]¹H-NMR (CDCl₃, δ): 1.48 (9H, s), 4.31 (1H, d, J=17.5Hz), 5.01 (1H,d, J=17.5Hz), 5.39 (1H, d, J=8.8Hz), 6.41 (1H, d, J=8.9Hz), 6.9-7.9 (7H,m)

[0774] Mass (APCI): 462 (M⁺+1)

Preparation 29-10

[0775](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-9-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-tert-butoxycarbonylamino-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0776] IR (Nujol, cm⁻¹): 1660

[0777]¹H-NMR(CDCl₃, δ): 1.46 (9H, s), 1.4-2.2 (10H, br), 3.2-3.5(2H, m),3.5-4.0 (2H, m), 4.36 (1H, d, J=16.1Hz), 5.24 (1H, d, J=16.1Hz), 5.42(1H, d, J=9.0Hz), 6.39 (1H, d, J=8.9Hz), 7.0-7.3 (3H, m), 7.3-7.5 (1H,m), 7.5-7.7 (1H, m), 7.7-7.9 (1H, m), 8.01 (1H, br, s)

[0778] Mass (APCI): 596 (M⁺+1)

Preparation 29-11

[0779] A mixture of(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-9-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-tert-butoxycarbonylamino-1H-1,4-benzodiazepin-2-one(660 mg) and 4N aqueous hydrochloric acid in ethyl acetate (3 ml) wasstirred at 0° C. for 5.5 hours. A saturated aqueous solution of sodiumbicarbonate and ethyl acetate were added to the reaction mixture. Theseparated organic layer was washed with water and brine, and then driedover sodium sulfate. The solvent was evaporated in vacuo to afford(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-9-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(549.0 mg) as a crystalline powder.

[0780] IR (Nujol, cm⁻¹): 1680, 1650

[0781]¹H-NMR (CDCl₃, δ): 1.4-2.2 (10H, m), 3.2-3.5 (2H, m), 3.5-4.0 (2H,m), 4.36 (1H, d, J=16.1 Hz), 4.61 (1H, br, s), 5.29 (1H, d, J=16.1Hz),7.0-7.4 (4H, m), 7.4-7.5 (1H, m), 7.5-7.7 (1H, m), 7.7-7.9 (1H, m)

[0782] Mass (APCI): 469 (M⁺+1)

Preparation 30-1

[0783](3RS)-2,3-Dihydro-1-tert-butylcarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0784] IR (Nujol, cm⁻¹): 1720, 1700, 1635

[0785]¹H-NMR (CDCl₃, δ): 1.13 (9H, s), 1.45 (9H, s), 2.39 (3H, s), 4.03(1H, d, J=17.1Hz), 5.09 (1H, d, J=17.1Hz), 5.40 (1H, d, J=9.0Hz), 6.36(1H, d, J=9.0Hz), 7.0-7.6 (6H, m), 7.7-7.9 (1H, m)

[0786] Mass (APCI): 482 (M⁺+1)

Preparation 30-2

[0787] A mixture of(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-tert-butylcarbonylmethyl-3-tert-butoxycarbonylamino-9-methyl-1H-1,4-benzodiazepin-2-one(130 mg) and 4N HCl in ethyl acetate (1 ml) was stirred at 0° C. for 5hours. Ethyl acetate and a saturated aqueous solution of sodiumbicarbonate were added to the reaction mixture. The separated organiclayer was washed with water and brine, and then dried over sodiumsulfate. The solvent was evaporated in vacuo to afford(3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-tert-butylcarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one(100 mg, 97.1%) as a crystalline powder.

[0788] IR (Nujol, cm⁻¹): 1720, 1670

[0789]¹H-NMR (CDCl₃, δ): 1.14 (9H, s), 2.39 (3H, s), 3.99 (1H, d,J=17.1Hz), 4.65 (1H, br, s), 5.16 (1H, d, J=17.1Hz), 7.0-7.6 (6H, m),7.7-7.9 (1H, m).

[0790] Mass (APCI): 382 (M⁺+1)

Preparation 31-1

[0791](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonylmethyl-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0792]¹H-NMR (CDCl₃, δ): 1.19 (3H, t, J=7.1Hz), 2.33 (3H, s), 2.56 (3H,s), 3.78 (1H, d, J=16.9Hz), 4.08 (2H, q, J=7.1Hz), 4.92 (1H, d,J=16.9Hz), 5.0-5.2 (2H, m), 5.2-5.3 (1H, m), 6.50 (1H, d, J=8.6Hz),7.2-7.5 (8H, m)

[0793] Mass (APCI): 424 (M⁺+1)

Preparation 31-2

[0794](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-4.

[0795] IR (Nujol, cm⁻¹): 1720, 1690, 1618

[0796]¹H-NMR (CDCl₃, δ): 2.29 (3H, s), 2.46 (3H, s), 3.72 (1H, d,J=17.1Hz), 4.91 (1H, d, J=17.1Hz), 5.0-5.1 (2H, m), 5.25 (1H, d,J=7.6Hz), 6.73 (1H, d, J=8.7Hz), 7.2-7.5 (8H, m), 7.90 (1H, m)

[0797] Mass (APCI): 396 (M⁺+1)

Preparation 31-3

[0798](3RS)-3-Benzyloxycarbonylamino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0799] IR (Nujol, cm⁻¹) 1720, 1675, 1650

[0800]¹H-NMR (CDCl₃,δ): 1.5-1.9 (8H, m), 1.9-2.1 (2H, m), 2.35 (3H, s),2.60 (3H, s), 3.2-3.4 (2H, m), 3.60 (1H, dd, J=4.7Hz and J=13.7Hz), 3.77(1H, d, J=15.8Hz), 3.87 (1H, d, J=5.0Hz and J=13.7Hz), 5.0-5.1 (2H, m),5.19 (1H, d, J=15.8Hz), 5.2-5.4 (1H, m), 6.52 (1H, d, J=8.7Hz), 7.2-7.5(8H, m)

[0801] Mass (APCI): 503 (M⁺+1)

Preparation 31-4

[0802](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0803] IR (Nujol, cm⁻¹) 3350, 3270, 1665, 1620

[0804]¹H-NMR (CDCl₃, δ): 1.4-1.9 (8H, m), 1.9-2.1 (2H, m), 2.35 (3H, s),2.58 (3H, s), 3.2-3.5 (2H, m), 3.5-3.9 (2H, br, m), 4.42 (1H, s), 5.23(1H, d, J=15.6Hz), 7.2-7.5 (3H, m)

[0805] Mass (APCI): 369 (M⁺+1)

Preparation 31-5

[0806](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5,9-dimethyl-2,3-dihydro-3-(imidazol-1-yl)carbonylamino-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 22.

[0807] IR (Nujol, cm⁻¹): 1720, 1685, 1650

[0808] Mass (APCI): 427 (M⁺+1)

[0809]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.39 (3H, s), 2.49 (3H, s),2.9-3.4 (2H, m), 3.6-3.9 (2H, m), 3.95 (1H, d, J=16.2Hz), 5.13 (1H, d,J=16.2Hz), 5.2-5.3 (1H, m), 7.0-7.1 (1H, m), 7.2-7.7 (3H, m), 7.86 (1H,br, s), 8.40 (1H, br, s), 9.71 (1H, d, J=7.2Hz)

Preparation 32

[0810] To a suspension ofN-{(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl}-N′-(3-methylphenyl)urea(140.5 mg) in methylene chloride (5 ml) was added m-chloroperbenzoicacid (m-CPBA, 72.5 mg, 1.5 eq.mol) portionwise under stirring at ambienttemperature. After stirring for 5.5 hours, an additional m-CPBA (48 mg)was added and the stirring was continued for 3.5 hours further. From theclear reaction mixture, methylene chloride was removed in vacuo and theresidue was dissolved in ethyl acetate. The solution was washed with anaqueous solution of sodium bicarbonate, water and brine. The organiclayer was dried over magnesium sulfate and evaporated to afford areddish oil, which was subjected to preparative thin layerchromatography on silica gel (60F254, 0.5 mm, 20×20 cm; Merck) developedwith a mixture of chloroform and methanol (10:1) to giveN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-4-oxido-3-yl]-N′-(3-methylphenyl)ureaas a white crystalline powder (69.5 mg, 48.0%).

[0811] mp: 244.1-245.6° C. (dec.)

[0812]¹H-NMR (CDCl₃+CD₃ OD, δ):1.53-1.73 (8H, m), 1.94 (1H, br, s), 2.05(1H, br, s), 2.25 (3H, s), 2.41 (3H, s), 2.56 (3H, s), 3.20-3.36 (2H,m), 3.54-3.81 (2H, m), 4.56 (2H, dd, J=15.8Hz, J=255.0Hz), 5.97 (1H, s),6.76-7.45 (9H, m)

[0813] APCI-MS (m/z): 518 (M⁺+1)

Preparation 33-1

[0814] 2′-Amino-3′-(N,N-dimethylamino)acetophenone was prepared in asimilar manner to that of Preparation 50-1.

[0815] IR (Nujol, cm⁻¹): 3450, 3320, 1640

[0816]¹H-NMR (CDCl₃, δ): 2.60 (3H, s), 2.64 (3H, s), 6.59 (1H, dd,J=7.7Hz and J=8.1Hz), 7.13 (1H, dd, J=1.3Hz and J=7.5Hz), 7.48 (1H, dd,J=1.3Hz and J=8.2Hz), 6.6-7.0 (2H, m)

[0817] Mass (APCI): 179 (M⁺+1)

Preparation 33-2

[0818](3RS)-3-Benzyloxycarbonylamino-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[0819] IR (Nujol, cm⁻¹) 1710, 1680

[0820]¹H-NMR(CDCl₃, δ): 2.46 (3H, s), 2.67 (6H, s), 5.0-5.2 (2H, m),6.56 (1H, d, J=8.1Hz), 7.1-7.4 (8H, m), 8.26 (1H, br, s)

[0821] Mass (APCI): 367 (M⁺+1)

Preparation 33-3

[0822] To a solution of(3RS)-3-benzyloxycarbonylamino-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one(820 mg) in N,N-dimethylformamide (5 ml) was added portionwise 60%sodium hydride suspended in oil (94 mg) under nitrogen stream andcooling in an ice-bath. The mixture was stirred under the sameconditions for 3 hours. N-Bromoacetyl-3-azabicyclo[3.2.2]nonane (578 g)was added to the reaction mixture at 0° C. The resultant mixture wasstirred at room temperature overnight. Ethyl acetate and water wereadded to the mixture. The separated organic layer was washed with watertwice and brine, and then dried over sodium sulfate. The solvent wasevaporated in vacuo to afford a pale yellow residue, which was subjectedto column chromatography on silica gel eluting with a mixture of tolueneand ethyl acetate (2:1). The fractions containing the desired productwere combined and evaporated in vacuo to give(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one(510 mg, 42.8% yield) as a crystalline powder.

[0823] IR (Nujol, cm⁻¹): 1715, 1680, 1650

[0824]¹H-NMR (CDCl₃, δ): 1.3-2.2 (10H, m), 2.58 (3H, s), 2.74 (6H, s),3.2-3.4 (2H, m), 3.4-3.8 (2H, m), 4.70 (1H, d, J=16.1Hz), 5.09 (1H, d,J=16.1Hz), 5.0-5.2 (2H, m), 5.2-5.4 (1H, m), 6.48 (1H, d, J=8.5Hz),7.0-7.4 (8H, m)

[0825] Mass (APCI): 532 (M⁺+1)

Preparation 33-4

[0826](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0827] IR (Nujol, cm⁻¹): 1680, 1640

[0828]¹H-NMR (CDCl₃, δ): 1.3-2.2 (10H, m), 2.35 (2H, m), 2.57 (3H, s),2.74 (6H, s), 3.2-3.8 (4H, m), 4.46 (1H, br, s), 4.69 (1H, d, J=16.1Hz),5.13 (1H, d, J=16.1Hz), 7.0-7.4 (3H, m)

[0829] Mass (APCI): 398 (M⁺+1)

Preparation 34-1

[0830] (3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-tert-butoxycarbonylmethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0831] IR (Nujol, cm⁻¹): 1720, 1680

[0832]¹H-NMR(CDCl₃, δ): 1.28 (9H, s), 2.36 (3H, s), 3.81 (1H, d,J=16.6Hz), 4.70 (1H, d, J=16.6Hz), 5.0-5.3 (2H, m), 5.42 (1H, d,J=8.6Hz), 6.67 (1H, d, J=8.6Hz), 7.0-7.6 (11H, m), 7.7-7.9 (1H, m)

[0833] Mass (APCI): 532 (M⁺+1)

Preparation 34-2

[0834](3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-tert-butoxycarbonylmethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0835]¹H-NMR(CDCl₃, δ): 1.29 (9H, s), 2.38 (3H, s), 3.79 (1H, d,J=16.6Hz), 4.58 (1H, s), 4.73 (1H, d, J=16.6Hz), 7.0-7.6 (6H, m),7.7-7.9 (1H, m)

[0836] Mass (APCI): 398 (M⁺+1)

Preparation 35-1

[0837](3RS)-1-(Adamantan-1-yl)carbonylmethyl-3-benzyloxycarbonyl-amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0838] IR (Nujol, cm⁻¹): 1710, 1670

[0839]¹H-NMR (DMSO-d₆, δ): 1.5-2.0 (15H, m), 2.40 (3H, s), 4.06 (1H, d,J=17.4Hz), 5.04 (2H, br, s), 5.16 (1H, d, J=8.5Hz), 5.21 (1H, d,J=17.5Hz), 7.03 (1H, d, J=8.7Hz), 7.0-7.8 (12H, m)

[0840] Mass (APCI): 594 (M⁺+1)

Preparation 35-2

[0841](3RS)-1-(Adamantan-1-yl)carbonylmethyl-3-amino-5-(2-fluorophenyl)-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0842] IR (Nujol, cm⁻¹): 1710, 1670

[0843]¹H-NMR(CDCl₃, δ): 1.5-2.3 (15H, m), 2.38 (3H, s), 3.95 (1H, d,J=17.1Hz), 4.59 (1H, s), 5.14 (1H, d, J=17.1Hz), 7.0-7.5 (6H, m),7.7-7.9 (1H, m)

[0844] Mass (APCI): 460 (M⁺+1)

Preparation 36-1

[0845](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1,5,9-trimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0846] IR (Nujol, cm⁻¹): 1710, 1665, 1620

[0847]¹H-NMR (CDCl₃, δ): 2.35 (3H, s), 2.43 (3H, s), 3.19 (3H, s), 5.06(1H, d, J=12.3Hz), 5.13 (1H, d, J=12.3Hz), 5.1-5.2 (1H, m), 6.60 (1H, d,J=8.3Hz), 7.1-7.5 (8H, m)

[0848] Mass (APCI): 352 (M⁺+1)

Preparation 36-2

[0849](3RS)-3-Amino-2,3-dihydro-1,5,9-trimethyl-1H-1,4-benzodiazepin-2-one wasprepared in a similar manner to that of Preparation 59-6.

[0850] IR (Neat, cm⁻¹): 3350, 1685, 1615

[0851]¹H-NMR(CDCl₃, δ): 2.36 (3H, s), 2.47 (3H, s), 3.18 (3H, s), 4.31(1H, d, J=1.3Hz), 7.1-7.4 (3H, m)

[0852] Mass (APCI): 218 (M⁺+1)

Preparation 37-1

[0853](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5,9-dimethyl-1-(2-methylphenacyl)-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0854] IR (Nujol, cm⁻¹) 1715, 1670

[0855]¹H-NMR (CDCl₃, δ): 2.29 (3H, s), 2.39 (3H, s), 2.51 (3H, s), 4.20(1H, d, J=17.0Hz), 5.0-5.2 (2H, m), 5.28 (1H, dd, J=1.5Hz and 8.7Hz),5.61 (1H, d, J=17.0Hz), 6.52 (1H, d, J=8.7Hz), 7.2-7.5 (11H, m), 7.5-7.6(1H, m)

[0856] Mass (APCI): 470 (M⁺+1)

Preparation 37-2

[0857](3RS)-3-Amino-1-(2-methylphenacyl)-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0858] IR (Nujol, cm⁻¹): 1670, 1615

[0859]¹H-NMR(CDCl₃, δ): 2.28 (3H, s), 2.41 (3H, s), 2.47 (3H, s), 4.18(1H, d, J=16.9Hz), 4.4 (1H, m), 5.64 (1H, d, J=16.9Hz), 7.1-7.6 (7H, m)

[0860] Mass (APCI): 336 (M⁺+1)

Preparation 38

[0861](3RS)-1-(Adamantan-1-yl)carbonylmethyl-3-amino-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0862] IR (Nujol, cm⁻¹): 1700, 1670

[0863]¹H-NMR(CDCl₃, δ): 1.6-2.3 (15H, br), 2.32 (3H, s), 2.61 (3H, s),3.74 (1H, d, J=17.2Hz), 4.4 (1H, m), 5.28 (1H, d, J=17.2Hz), 7.1-7.5(3H, m)

[0864] Mass (APCI): 380 (M⁺+1)

Preparation 39-1

[0865](3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0866] IR (Neat, cm⁻¹): 1720, 1670

[0867]¹H-NMR (CDCl₃, δ): 1.1-2.0 (10H, m), 2.2-2.4 (1H, m), 2.32 (3H,s), 2.61 (3H, s), 3.74 (1H, d, J=17.2Hz), 5.0-5.2 (3H, m), 5.24 (1H, d,J=7.3Hz), 6.46 (1H, d, J=8.8Hz), 7.1-7.5 (8H, m)

[0868] Mass (APCI): 462 (M⁺+1)

Preparation 39-2

[0869](3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0870] IR (Neat, cm⁻¹): 1715, 1670

[0871]¹H-NMR (CDCl₃, δ): 1.1-2.0 (10H, m), 2.0-2.4 (1H, m), 2.32 (3H,s), 2.60 (3H, s), 3.72 (1H, d, J−17.2Hz), 4.4 (1H, m), 5.13 (1H, d,J=17.2Hz), 7.1-7.5 (3H, m)

[0872] Mass (APCI): 328 (M⁺+1)

Preparation 40-1

[0873](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-methylcarbonylmethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0874] IR (Nujol, cm⁻¹): 1705, 1660

[0875]¹H-NMR (DMSO-d₆, δ): 2.00 (3H, s), 2.38 (3H, s), 4.23 (1H, d,J=17.6Hz), 4.91 (1H, d, J=17.6Hz), 5.05 (2H, br, s), 5.18 (1H, d,J=8.5Hz), 7.04 (1H, d, J=7.6Hz), 7.1-7.7 (1H, m), 8.42 (1H, d, J=8.5Hz)

[0876] Mass (APCI): 474 (M⁺+1)

Preparation 40-2

[0877](3RS)-3-Amino-5-(2-fluorophenyl)-2,3-dihydro-9-methyl-1-methylcarbonylmethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0878] IR (Nujol, cm⁻¹): 1720, 1670

[0879]¹H-NMR(CDCl₃, δ): 2.07 (3H, s), 2.39 (3H, s), 3.87 (1H, d,J=17.0Hz), 4.60 (1H, s), 4.96 (1H, d, J=17.0Hz), 7.0-7.6 (6H, m),7.7-7.9 (1H, m)

[0880] Mass (APCI): 340 (M⁺+1)

Preparation 41

[0881](3RS)-3-Amino-2,3-dihydro-1-tert-butylcarbonylmethyl-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0882] IR (Nujol, cm⁻¹): 1710, 1670, 1615

[0883]¹H-NMR(CDCl₃, δ): 1.13 (9H, s), 2.32 (3H, s), 2.61 (3H, s), 3.79(1H, d, J=17.2Hz), 4.4 (1H, m), 5.29 (1H, d, J=17.2Hz), 7.1-7.5 (3H, m)

[0884] Mass (APCI): 302 (M⁺+1)

Preparation 42-1

[0885](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(3-nitrophenacyl)-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0886] mp: 86.1-89.0° C.

[0887] IR (Nujol, cm⁻¹): 1700, 1670

[0888]¹H-NMR (DMSO-d₆, δ): 4.51 (1H, d, J=17.0Hz), 5.52 (1H, d,J=8.6Hz), 5.72 (1H, d, J=17.0Hz), 6.61 (1H, d, J=8.7Hz), 7.0-7.8 (12H,m), 7.8-8.0 (1H, m), 8.1-8.3 (1H, m), 8.3-8.5 (1H, m), 8.68 (1H, m)

[0889] Mass (APCI): 581 (M⁺+1)

Preparation 42-2

[0890](3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(3-nitrophenacyl)-1H-1,4-benzodiazepin-2-onehydrobromide was prepared in a similar procedure to that of Preparation43.

[0891] IR (Nujol, cm⁻¹): 1678

[0892]¹H-NMR (DMSO-d₆, δ): 2.50 (3H, s), 5.04 (1H, d, J=17.9Hz), 5.30(1H, s), 5.91 (1H, d, J=17.9Hz), 7.12 (1H, d, J=7.6Hz), 7.3-7.5 (3H, m),7.5-8.0 (4H, m), 8.3-8.5 (2H, m), 8.65 (1H, m), 9.05 (2H, m)

[0893] Mass (APCI): 447 (free, M⁺+1)

Preparation 43

[0894] A mixture of(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-nitrophenacyl)-1H-1,4-benzodiazepin-2-one(300 mg) and 30% hydrobromic acid in acetic acid (3 ml) was stirred atroom temperature for 4.5 hours. Water and ice were added to the reactionmixture to afford powder, which was collected by filtration, and washedwith water to give(3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-nitrophenacyl)-1H-1,4-benzodiazepin-2-onehydrobromide (227 mg, 81.8%).

[0895] IR (Nujol, cm⁻¹): 1670

[0896]¹H-NMR (DMSO-d₆, δ): 2.43 (3H, s), 4.79 (1H, d, J=18.3Hz), 5.32(1H, s), 5.56 (1H, d, J=18.3Hz), 7.12 (1H, d, J=7.6Hz), 7.2-7.4 (3H, m),7.5-7.7 (3H, br), 7.7-8.0 (3H, m), 8.12 (1H, d, J=7.8Hz), 9.04 (2H, m)

[0897] Mass (APCI): 447 (free, M⁺+1)

Preparation 44-1

[0898](3RS)-3-Benzyloxycarbonylamino-2,3-dithydro-1-ethylcarbonylmethyl-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0899] IR (Nujol, cm⁻¹): 1715, 1670, 1620

[0900]¹H-NMR (CDCl₃, δ): 1.00 (3H, t, J=7.3Hz), 2.32 (3H, s), 2.3-2.5(2H, m), 2.60 (3H, s), 3.72 (1H, d, J=17.2Hz), 5.0-5.2 (3H, m), 5.25(1H, dd, J=1.4Hz and J=8.7Hz), 6.46 (1H, d, J=8.6Hz), 7.2-7.5 (8H, m)

[0901] Mass (APCI): 408 (M⁺+1)

Preparation 44-2

[0902](3RS)-3-Amino-2,3-dihydro-1-ethylcarbonylmethyl-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0903] IR (Neat, cm⁻¹): 1720

[0904]¹H-NMR (CDCl₃, δ): 1.00 (3H, t, J=7.3Hz), 2.32 (3H, s), 2.3-2.6(2H, br, m), 2.60 (3H, s), 3.70 (1H, d, J=17.1Hz), 4.40 (1H, m), 5.06(1H, d, J=17.1Hz), 7.1-7.5 (3H, m)

[0905] Mass (APCI): 274 (M⁺+1)

Preparation 45-1

[0906] 2-Isobutyryl-6-methylaniline was prepared in a similar manner tothat of Preparation 50-1.

[0907] mp: 47-49° C.

[0908] IR (Nujol, cm⁻¹): 3470, 3320, 1638, 1607, 1580, 1550, 1422, 1380,1230, 1094, 1011, 984, 745

[0909]¹H-NMR (CDCl₃, δ): 1.21 (6H, d, J=6.8Hz), 2.16 (3H, s), 3.62 (1H,hept, J=6.8Hz), 6.4 (1H, br), 6.60 (1H, t, J=7.3Hz), 7.19 (1H, d,J=7.3Hz), 7.69 (1H, d, J=7.3Hz)

[0910] APCI-MS (m/z) 178 (M⁺+1)

Preparation 45-2

[0911] To a solution of N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine(10.77 g) in dry tetrahydrofuran (80 ml) were added oxalyl chloride(2.88 ml) and one drop of dimethylformamide at 0° C. under stirring andnitrogen stream. The mixture was stirred for 2 hours under the sameconditions. To the reaction mixture was added dropwise a mixture of2-isobutyryl-6-methylaniline (5.32 g) and N-methylmorpholine (6.68 g) indry tetrahydrofuran (30 ml) for 20 minutes under the same conditions.After the addition was completed, the mixture was stirred at ambienttemperature for 0.5 hour. The resultant precipitate was filtered off andthe filtrate and washings were combined and evaporated in vacuo. Theresidue was dissolved in 20% methanolic ammonia (80 ml) and stirred atambient temperature overnight. The resultant precipitate was collectedby filtration and washed with cold methanol to give the first crop ofthe desired product (3.25 g, 29.6%). The filtrate and the washings werecombined and evaporated in vacuo to afford a residue, which wasdissolved in ethyl acetate and washed with 1N-NaOH aqueous solution andwater. The organic layer was dried over magnesium sulfate and evaporatedto give a residual oil, which was dissolved in acetic acid (70 ml) andtreated with ammonium acetate (7.0 g) for 4 hours at ambienttemperature. After removal of acetic acid in vacuo, the residue wasdissolved in ethyl acetate and washed with diluted hydroxide aqueoussolution and water successively. The organic layer was dried overmagnesium sulfate and evaporated in vacuo to give an orange oil, whichwas triturated in methanol overnight to afford the second crop of thedesired product (1.01 g, 9.2%),(3RS)-3-benzyloxycarbonylamino-5-isopropyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.

[0912] mp: 169.1-172.8° C.

[0913] IR (Nujol, cm⁻¹): 3300 (sh), 3200, 1710, 1690, 1614, 1514, 1398,1367, 1055, 990, 798, 750, 687

[0914]¹H-NMR (CDCl₃, δ): 0.91 (3H, d, J=7.0Hz), 1.27 (3H, d, J=7Hz),2.36 (3H, s), 3.13 (1H, hept, J=7.0Hz), 5.11 (2H, s), 5.15 (1H, d,J=8.4Hz), 6.46 (1H, d, J=8.4Hz), 7.1-7.45 (8H, m), 8.59 (1H, s)

[0915] APCI-MS (m/z): 366 (M⁺+1)

Preparation 45-3

[0916](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0917]¹H-NMR (CDCl₃, δ): 1.1-1.4 (3H, m), 2.34 (3H, s), 3.1-3.4 (1H, m),3.82 (1H, d, J=16.7Hz), 4.12 (2H, q, J=7.1Hz), 4.72 (1H, d, J=16.7Hz),5.0-5.2 (2H, m), 5.2-5.3 (1H, m), 6.49 (1H, d, J=8.6Hz), 7.2-7.5 (8H, m)

[0918] Mass (APCI): 452 (M⁺+1)

Preparation 45-4

[0919](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-4.

[0920]¹H-NMR (CDCl₃, δ): 1.0-1.4 (6H, m), 2.32 (3H, br, s), 3.1-3.3 (1H,m), 3.84 (1H, d, J=17.0Hz), 4.76 (1H, d, J=17.0Hz), 5.0-5.2 (2H, m),5.22 (1H, d, J=8.1Hz), 6.54 (1H, d, J=8.7Hz), 7.2-7.5 (8H, m)

[0921] Mass (APCI): 424 (M⁺+1)

Preparation 45-5

[0922](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[0923] IR (Nujol, cm⁻¹): 1720, 1650

[0924]¹H-NMR (CDCl₃, δ): 1.22 (3H, d, J=7.1Hz), 1.33 (3H, d, J=6.6Hz),1.4-1.9 (8H, m), 1.9-2.1 (2H, m), 2.36 (3H, br, s), 3.1-3.9 (5H, m),3.86 (1H, d, J=15.5Hz), 5.0-5.2 (2H, m), 5.24 (1H, d, J=8.2Hz), 6.50(1H, d, J=8.7Hz), 7.2-7.5 (8H, m)

[0925] Mass (APCI): 531 (M⁺+1)

Preparation 45-6

[0926](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0927] IR (Nujol, cm⁻¹): 3330, 3250, 1660, 1630

[0928]¹H-NMR (CDCl₃, δ): 1.2-1.3 (3H, m), 1.34 (3H, d, J=6.6Hz), 1.5-2.3(10H, m), 2.36 (3H, s), 3.21 (1H, m), 3.4-3.9 (4H, m), 3.87 (1H, d,J=15.5Hz), 4.38 (1H, s), 5.02 (1H, d, J=15.5Hz), 7.1-7.5 (3H, m)

[0929] Mass (APCI): 397 (M⁺+1)

Preparation 46-1

[0930](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5,9-dimethyl-1-methylcarbonylmethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0931] IR (Neat, cm⁻¹): 1720, 1670

[0932]¹H-NMR (CDCl₃, δ): 2.06 (3H, s), 2.32 (3H, s), 2.60 (3H, s), 3.75(1H, d, J=17.4Hz), 5.0-5.2 (3H, m), 5.25 (1H, dd, J=1.4Hz and 8.7Hz),6.47 (1H, d, J=8.6Hz), 7.2-7.5 (8H, m)

[0933] Mass (APCI): 394 (M⁺+1)

Preparation 46-2

[0934](3RS)-3-Amino-2,3-dihydro-5,9-dimethyl-1-methylcarbonylmethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0935] IR (Neat, cm⁻¹): 1720, 1650

[0936]¹H-NMR (CDCl₃, δ): 2.07 (3H, s), 2.32 (3H, s), 2.59 (3H, s), 3.72(1H, d, J=17.4Hz), 5.4 (1H, m), 5.08 (1H, d, J=17.3Hz), 7.1-7.5 (3H, m)

[0937] Mass (APCI): 260 (M⁺+1)

Preparation 47-1

[0938](3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-1-cyclopropyl-carbonylmethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0939]¹H-NMR(CDCl₃, δ): 0.8-1.2 (4H, m), 1.2-2.0 (10H, m), 2.0-2.2 (1H,m), 2.34 (3H, br, s), 2.84 (1H, m), 4.01 (1H, d, J=17.1Hz), 4.96 (1H, d,J=17.1Hz), 5.0-5.2 (2H, m), 5.21 (1H, d, J=8.2Hz), 6.49 (1H, d,J=8.7Hz), 7.2-7.5 (8H, m)

[0940] Mass (APCI): 488 (M⁺+1)

Preparation 47-2

[0941](3RS)-3-Amino-5-cyclohexyl-1-cyclopropylcarbonylmethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0942] IR (Nujol, cm⁻¹): 1675

[0943]¹H-NMR (CDCl₃, δ): 0.8-2.0 (14H, m), 2.0-2.2 (1H, m), 2.34 (3H,s), 2.7-2.9 (1H, m), 4.01 (1H, d, J=17.1Hz), 4.39 (1H, br, s), 4.95 (1H,d, J=17.1Hz), 7.1-7.5 (3H, m)

[0944] Mass (APCI): 354 (M⁺+1)

Preparation 48

[0945](3RS)-3-Amino-2,3-dihydro-1-ethoxycarbonylmethyl-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0946] IR (Neat, cm⁻¹): 3380, 3300, 1738, 1680, 1620

[0947]¹H-NMR(CDCl₃, δ): 1.19 (3H, t, J=7.1Hz), 2.24 (2H, m), 2.33 (3H,s), 2.55 (3H, s), 3.75 (1H, d, J=16.9Hz), 4.09 (2H, q, J=7.1Hz), 4.40(1H, br, s), 4.94 (1H, d, J=16.9Hz), 7.1-7.7 ( 3H, m)

[0948] Mass (APCI): 290 (M⁺+1)

Preparation 49-1

[0949](3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1-(1-triphenylmethylimidazol-4-yl)methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0950] IR (Nujol, cm⁻¹): 720, 1675

[0951]¹H-NMR(CDCl₃, δ): 1.0-2.2 (10H, m), 2.35 (3H, br, s), 2.67 (1H,m), 4.23 (1H, d, J=14.5Hz), 5.0-5.2 (3H, br), 5.32 (1H, d, J=14.4Hz),6.51 (1H, d, J=8.3Hz), 6.77 (1H, br, s), 6.9-7.5 (24H, m)

[0952] Mass (FAB): 728 (M⁺+1)

Preparation 49-9

[0953] A mixture of(3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1-(1-triphenylmethylimidazol-4-yl)methyl-1H-1,4-benzodiazepin-2-one(0.5 g) and 30% hydrobromic acid in acetic acid (2.0 ml) was stirred atroom temperature overnight. The reaction mixture was poured into amixture of an ice and ethyl acetate under stirring. The separated waterlayer was washed with ethyl acetate once, and neutralized with asaturated aqueous solution of sodium bicarbonate. The resultant aqueousmixture was extracted with ethyl acetate and the extract was dried oversodium sulfate. Removal of the solvent in vacuo afforded(3RS)-3-amino-5-cyclohexyl-2,3-dihydro-1-(imidazol-4-yl)methyl-9-methyl-1H-1,4-benzodiazepin-2-one(174 mg, 72.1%) as a crystalline powder.

[0954] IR (Nujol, cm⁻¹): 1670, 1610

[0955]¹H-NMR (CDCl₃, δ): 0.9-2.0 (10H, m), 2.42 (3H, s), 2.5-2.7 (1H,m), 4.19 (1H, d, J=14.7Hz), 4.29 (1H, br, s), 5.31 (1H, d, J=14.7Hz),6.73 (1H, br, s), 7.1-7.5 (6H, m)

[0956] Mass (APCI): 352 (M⁺+1)

Preparation 50-1

[0957] To a mixture of 2-toluidine (32.8 g, 0.30 ml) and acetonitrile(6.22 g, 0.15 mol) in dry toluene (200 ml) was added 1N-solution ofboron trichloride in toluene (150 ml) dropwise under stirring andcooling in an ice-bath for 2 hours. After the addition was completed,the mixture was stirred for 1 hour at ambient temperature and cooledagain. To the cooled mixture was added aluminum chloride (20.0 g, 0.15mol) portionwise. The resultant mixture was stirred at ambienttemperature for 1 hour and refluxed for 5 hours. After cooling thereaction mixture in an ice-bath, 2N-HCl (200 ml) was added. The mixturewas then refluxed for 2.5 hours. After cooling the mixture, ethylacetate was added. The separated organic layer was washed with watertwice and dried over magnesium sulfate. Removal of the solvent in vacuogave crystals, which was washed with n-hexane with stirring andcollected by filtration to give 2-acetyl-6-methylaniline as a yellowcrystal (8.91 g, 39.8%).

[0958] mp: 51.1-52.9° C.

[0959] IR (Nujol, cm⁻¹): 3410, 3300, 1630 (sh), 1610, 960, 740

[0960]¹H-NMR (CDCl₃, δ): 2.16 (3H, s), 2.59 (3H), 6.4 (1H, br), 6.59(1H, t, J=7.9Hz), 7.19 (1H, d, J=7.9Hz), 7.63 (1H, d, J=7.9Hz)

[0961] APCI-MS (m/z): 150 (M⁺+1)

Preparation 50-2

[0962] To a solution of N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine(14.11 g) in dry tetrahydrofuran (100 ml) were added oxalyl chloride(3.77 ml) and dimethylformamide (3 drops) under stirring at 0° C. in anice-salt bath under nitrogen stream. After the mixture was stirred underthe same conditions for 2 hours, a mixture of 2-acetyl-6-methylaniline(4.30 g) and N-methylmorpholine (8.74 g) in tetrahydrofuran (20 ml) wasadded dropwise for 20 minutes. After the addition was completed, themixture was allowed to warm to ambient temperature with stirring.Tetrahydrofuran was removed in vacuo and the residue was dissolved inethyl acetate. The mixture was washed with water twice and dried overmagnesium sulfate. Removal of the solvent gave an intermediate productas an oil, to which was added 20% methanolic ammonia (75 ml) and stirredat ambient temperature overnight. The resultant precipitate wascollected by filtration and washed with cold methanol and diisopropylether successively, and dried to give(3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-oneas a white crystalline powder (6.17 g, 63.5%).

[0963] mp: 238-239.5° C.

[0964] IR (Nujol, cm⁻¹): 3210, 1718, 1690, 1678, 1628, 1059, 742, 699

[0965]¹H-NMR (CDCl₃, δ): 2.36 (3H, s), 2.46 (3H, s), 5.11 (2H, s), 5.14(1H, d, J=8.3Hz), 6.50 (1H, d, J=8.3Hz), 7.13-7.47 (8H, m), 8.48 (1H, s)

[0966] APCI-MS (m/z): 338 (M⁺+1)

Preparation 50-3

[0967] To a suspension of(3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(3.22 g) in methylene chloride (50 ml) was added m-chloroperbenzoic acid(2.50 g, 1.5 eq.mol) portionwise under stirring at ice-bath cooling. Themixture was stirred for 3 days at ambient temperatures. From thereaction mixture methylene chloride was removed in vacuo and to theresidue was added an aqueous solution of sodium bicarbonate and stirredfor several minutes. The mixture was extracted with ethyl acetate twiceand the combined extract was washed with aqueous sodium bicarbonate,water twice and brine. The organic layer was dried over magnesiumsulfate and evaporated in vacuo to afford an amorphous mass, which wastriturated in methanol and collected by filtration to give(3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide(2.59 g) as a crystalline powder. From the mother liquid, the secondcrop (0.25 g) of the desired powder was prepared by crystallization in amixture of methanol and diisopropyl ether (3:1).

[0968]¹H-NMR (DMSO-d₆, δ): 2.38 (6H, s), 5.08 (2H, dd, J=12.9Hz,14.8Hz), 5.45 (1H, d, J=9.3Hz), 7.15-7.52 (8H, m), 7.89 (1H, d,J=9.3Hz), 10.49 (1H, s)

[0969] APCI-MS (m/z): 354 (M⁺+1)

Preparation 50-4

[0970] A mixture of(3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide(2.83 g) and acetic anhydride (7.6 ml, 10 eq.mol) in methylene chloride(60 ml) was stirred for 4 days. From the reaction mixture methylenechloride was removed in vacuo. To the residue was added a mixture (60ml) of diisopropyl ether and n-hexane (1:1). The resultant crystallinepowder was collected by filtration and washed with diisopropyl ether togive(3RS)-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepine-2-one(2.26 g, 71.1%) as a crystalline powder.

[0971]¹H-NMR (CDCl₃, δ): 2.01 (3H, s), 2.36 (3H, s), 4.95-5.29 (5H, m),6.48 (1H, d, J=8.3Hz), 7.12-7.47 (8H, m), 7.94 (1H, s)

[0972] APCI-MS (m/z): 396 (M⁺+1)

[0973] IR (Nujol, cm⁻¹): 3200, 1740, 1686

Preparation 50-5

[0974] To a solution of(3RS)-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(2.24 g) in dimethylformamide (40 ml) was added portionwise sodiumhydride (60% suspension in mineral oil, 0.227 g) under stirring andice-bath cooling. After the addition was completed, the suspension wasstirred for 1 hour at ambient temperature. Then to the mixture afterice-bath cooling again was added dropwise a solution of t-butylbromoacetate (1.11 g) in dimethylformamide (5 ml). The mixture wasstirred for 10 minutes under cooling and for 3.5 hours at ambienttemperature.

[0975] The reaction mixture was poured into ice-water and extracted withethyl acetate. The extract was washed with water three times and driedover magnesium sulfate. Removal of the solvent afforded(3RS)-3-benzyloxycarbonylamino-1-t-butoxycarbonylmethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(2.75 g, 95.2%) as an amorphous mass which was used in a followingreaction without further purification.

[0976]¹H-NMR (CDCl₃, δ) :1.37 (9H, s), 2.09 (3H, s), 2.34 (3H, s), 4.22(2H, dd, J=16.8Hz, 210.1Hz), 5.09 (2H, s), 5.20 (2H, s), 5.29 (1H, d,J=8.6Hz), 6.52 (1H, d, J=8.6Hz), 7.25-7.52 (8H, m)

[0977] APCI-MS (m/z): 510 (M⁺+1)

Preparation 50-6

[0978] To a solution of(3RS)-3-benzyloxycarbonylamino-1-t-butoxycarbonylmethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(3.02 g) in methylene chloride (45 ml) was added trifluoroacetic acid(4.6 ml) under stirring at ambient temperature. The mixture was stirredfor 20 hours under the same conditions. Methylene chloride was removedin vacuo and the residue was dissolved in ethyl acetate. The solutionwas washed with water four times and dried over magnesium sulfate.Removal of the solvent afforded an amorphous mass (2.82 g), which wassubjected to column chromatography on silica gel eluting with a mixtureof chloroform and methanol (30:1). The fractions containing the desiredproduct were combined and evaporated to give(3RS)-3-benzyloxycarbonylamino-1-carboxymethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(1.89 g, 70.3%) as a crystalline powder.

[0979] IR (Nujol, cm⁻¹): 3300, 2800-2200 (br), 1740 (sh), 1720, 1690,1375, 1230, 1060, 750

[0980]¹H-NMR (DMSO-d₆, δ): 2.04 (3H, s), 2.33 (3H, s), 4.25 (2H, dd,J=17.0Hz, 139.4Hz), 4.96 (1H, d, J=8.32Hz), 5.02 (2H, s), 5.17 (2H, dd,J=14.4Hz, 57.4Hz), 7.3-7.65 (8H, m), 8.31 (1H, d, J=8.32Hz)

[0981] APCI-MS (m/z): 454 (M⁺+1)

Preparation 50-7

[0982] A mixture of(3RS)-3-benzyloxycarbonylamino-1-carboxymethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(343.0 mg), 3-azabicyclo[3.2.2]nonane (106.3 mg), 1-hydroxybenzotriazole(HOBT, 112.4 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (WSCD, 160.3 mg) and triethylamine (84.1 mg) indimethylformamide (7 ml) was stirred for 12 hours at ambienttemperature. The reaction mixture was poured into water and the mixturewas extracted with ethyl acetate twice. The organic extract was washedwith water three times and dried over magnesium sulfate. Removal of thesolvent afforded an oil (0.45 g), which was pulverized in diisopropylether and collected by filtration to give(3RS)-3-benzyloxycarbonylamino-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(339.0 mg, 80.0%) as a light yellow crystalline powder.

[0983] IR (Nujol, cm⁻¹): 3370, 1751, 1729, 1677, 1642, 1508, 1230, 1056,760

[0984]¹H-NMR (DMSO-d₆, δ): 1.4-1.8 (8H, m), 1.85-2.15 (2H, m), 2.07 (3H,s), 2.37 (3H, s), 3.04-3.31 (2H, m), 3.60-3.82 (2H, m), 4.68 (2H, dd,J=14.7Hz, 288.3Hz), 4.90-5.14 (5H, m), 7.34-7.62 (8H, m), 8.26 (1H, d,J=8.6Hz)

[0985] APCI-MS (m/z): 561 (M⁺+1)

Preparation 50-8

[0986] A mixture of(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(320 mg), ammonium formate (144 mg) and 10% Pd-C(wet) (80 mg) in 99%ethanol (5 ml) was stirred for 4 hours. The catalyst was removed byfiltration through Celite® and the filtrate and the washings werecombined and evaporated in vacuo to afford a residue, which wassubjected to column chromatography on silica gel eluting with a mixtureof chloroform and methanol (20:1). The fractions containing the desiredproduct were combined and evaporated to give(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-oneas an amorphous mass (178.8 mg, 85.1%).

[0987]¹H-NMR (CDCl₃, δ): 1.55-1.77 (8H, m), 1.95-2.17 (2H, m), 2.35 (3H,s), 2.57 (3H, m), 3.29(2H, br, s), 3.36 (2H, m), 3.56-3.86 (2H, m), 4.44(1H, s), 4.50 (2H, dd, J=15.7Hz, 295.5Hz), 7.18-7.40 (3H, m)

[0988] APCI-MS (m/z): 369 (M⁺+1)

Preparation 51-1

[0989](3RS)-1-(2-Acetylbenzyl)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[0990] IR (Nujol, cm⁻¹): 1660

[0991]¹H-NMR (CDCl₃, δ): 1.2-2.2 (10H, m), 2.38 (3H, s), 2.41 (3H, s),2.8-3.0 (1H, m), 4.21 (1H, d, J=17.1Hz), 5.0-5.2 (2H, m), 5.28 (1H, d,J=8.2Hz), 5.40 (1H, d, J=17.1Hz), 6.51 (1H, d, J=8.6Hz), 7.2-7.5 (11H,m), 7.60 (1H, d, J=77Hz)

[0992] Mass (APCI): 538 (M⁺+1)

Preparation 51-2

[0993](3RS)-1-(2-Acetylbenzyl)-3-amino-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[0994]¹H-NMR (CDCl₃, δ): 1.2-2.3 (10H, m), 2.37 (3H, s), 2.38 (3H, s),2.8-3.0 (1H, m), 4.21 (1H, d, J=17.0Hz), 4.43 (1H, br, s), 5.39 (1H, d,J=17.0Hz), 5.2-5.6 (6H, m), 7.6-7.7 (1H, m)

[0995] Mass (APCI): 404 (M⁺+1)

Preparation 52-1

[0996] To a solution of 3-azabicyclo[3.2.2]nonane (1.1 g) andtriethylamine (0.88 g) in methylene chloride (25 ml) was addedportionwise 2-chloroacetyl-6-methylaniline (1.47 g) under stirring andcooling in an ice-bath. After the addition was completed, the mixturewas stirred at ambient temperature overnight. Removal of the solventafforded a residue, which was dissolved in ethyl acetate and washed withwater and brine. The organic layer was dried over magnesium sulfate andevaporated in vacuo to give a crystalline mass, which was pulverized ina mixture of n-hexane and diisopropyl ether. A dark yellow crystal wascollected by filtration to give2-[(3-azabicyclo[3.2.2]non-3-yl)acetyl]-6-methylaniline (1.92 g, 88.2%).

[0997] IR (Nujol, cm⁻¹): 3440, 3325, 1630, 1608, 1580, 1552, 1374, 1312,1136, 1000, 944, 868, 857, 749

[0998]¹H-NMR (CDCl₃, δ): 1.48-1.9 (10H, m), 2.16 (3H, s), 2.68 (4H, d,J=4.2Hz), 3.68 (2H, s), 6.38 (1H, br), 6.58 (1H, t, J=7.3Hz), 7.19 (1H,d, J=7.3Hz), 8.10 (1H, d, J=7.3Hz)

[0999] APCI-MS (m/z): 273 (M⁺+1)

Preparation 52-2

[1000](3RS)-3-Benzyloxycarbonylamino-5-(3-azabicyclo[3.2.2]non-3-yl)methyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[1001] mp: 149.2-151.4° C.

[1002] IR (Nujol, cm⁻¹): 3400 (sh), 3220, 1718, 1700, 1681, 1532, 1374,1058, 980, 778, 749, 691

[1003]¹H-NMR (CDCl₃, δ): 1.2-1.8 (10H, m), 2.36 (3H, s), 2.35-2.7 (4H,m), 3.45 (1H, br, d, J=14.3Hz), 3.90 (1H, d, J=14.3Hz), 5.11 (2H, s),5.19 (1H, d, J=8.2Hz), 6.54 (1H, d, J=8.2Hz), 7.1-7.8 (8H, m), 8.02 (1H,s)

[1004] APCI-MS (m/z): 461 (M⁺+1)

Preparation 52-3

[1005](3RS)-5-[(3-Azabicyclo[3.2.2]non-3-yl)methyl]-3-benzyloxycarbonylamino-2,3-dihydro-1,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[1006] IR (Nujol, cm⁻¹): 1720, 1670, 1620

[1007]¹H-NMR (CDCl₃, δ): 1.2-1.8 (10H, m), 2.35 (3H, s), 2.4-2.7 (4H,m), 3.15 (3H, s), 3.3-3.5 (1H, br, s), 3.9-4.1 (1H, br, s), 5.0-5.2 (2H,m), 5.23 (1H, d, J=8.4Hz), 6.64 (1H, d, J=8.5Hz), 7.2-7.6 (8H, m)

[1008] Mass (APCI): 475 (M⁺+1)

Preparation 52-4

[1009](3RS)-3-Amino-5-[(3-azabicyclo[3.2.2]non-3-yl)methyl]-2,3-dihydro-1,9-dimethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[1010]¹H-NMR (CDCl₃, δ): 1.2-1.8 (10H, m), 2.35 (3H, s), 2.3-2.6 (4H,m), 3.15 (3H, s), 3.2-3.4 (1H, m), 3.9-4.1 (1H, br, s), 4.40 (1H, m),3.2-3.6 (3H, m)

[1011] Mass (APCI): 341 (M⁺+1)

Preparation 53-1

[1012] To a solution of 2-chloroacetyl-6-methylaniline (1.84 g) inmethanol (50 ml) was added 28% methanolic sodium methoxide (5.79 g, 3eq.mol.) under stirring and cooling in an ice-bath. The mixture wasstirred for 0.5 hour under cooling and at ambient temperature overnight.Methanol was removed in vacuo to afford a residue, which was dissolvedin ethyl acetate and washed with water and brine successively. Theorganic layer was dried over magnesium sulfate and evaporated in vacuoto give an oil which was subjected to column chromatography on silicagel eluting with chloroform. The fractions containing the desiredproduct were combined and evaporated to give2-methoxyacetyl-6-methylaniline (1.07 g, 59.7% yield) as an oil.

[1013] IR (Film, cm⁻¹): 3410, 3340, 1655, 1620 (sh), 1610, 1585, 1560,1460, 1429, 1380, 1235, 1200, 1120, 1025, 982, 963, 930, 770 (sh), 744

[1014]¹H-NMR (CDCl₃, δ): 2.17 (3H, s), 3.51 (3H, s), 4.70 (2H, s), 6.41(1H, br), 6.58 (1H, t, J=7.3Hz), 7.19 (1H, d, J=7.3Hz), 7.49 (1H, d,J=7.3Hz)

[1015] APCI-MS (m/z): 180 (M⁺+1)

Preparation 53-2

[1016](3RS)-3-Benzyloxycarbonylamino-5-methoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[1017] IR (Nujol, cm⁻¹): 3250 (sh), 3210, 1719, 1696, 1685 (sh), 1530,1394, 1374, 1085, 1060, 985, 970, 780, 750

[1018]¹H-NMR (CDCl₃, δ): 2.37 (3H, s), 3.31 (3H, s), 4.50 (2H, dd,J=13.5Hz, J=49.8Hz), 5.11 (2H, s), 5.18 (1H, br, d), 6.58 (1H, br, d),7.15-7.6 (8H, m), 8.30 (1H, s)

[1019] APCI-MS (m/z): 368 (M⁺+1)

Preparation 53-3

[1020](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl-5-methoxymethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[1021]¹H-NMR(CDCl₃, δ): 1.22 (3H, t, J=7.1Hz), 2.34 (3H, br, s),3.46-3.48 (3H, m), 3.6-4.0 (2H, m), 4.12 (2H, q, J=7.1Hz), 4.0-4.3 (1H,br), 4.8-5.1 (1H, br, s), 5.1-5.3 (2H, m), 5.3-5.7 (1H, m), 6.5-6.8 (1H,m), 7.2-7.6 (8H, m)

[1022] Mass (APCI): 454 (M⁺+1)

Preparation 53-4

[1023](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-9-methyl-5-methoxymethyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-4.

[1024] IR (Neat, cm⁻¹): 1720, 1680

[1025]¹H-NMR (CDCl₃, δ): 2.34 (3H, s), 3.4-3.9 (6H, m), 5.0-5.3 (2H, m),5.4-5.7 (1H, m), 6.6-6.8 (1H, m), 7.2-7.6 (8H, m)

[1026] Mass (APCI): 426 (M⁺+1)

Preparation 53-5

[1027](3RS)-1-1(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-5-methoxymethyll-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[1028]¹H-NMR (CDCl₃, δ): 1.4-1.9 (8H, m), 1.9-2.2 (2H, m), 2.36 (3H, s),3.2-3.4 (2H, m), 3.49 (3H, s), 3.5-3.7 (2H, br), 3.7-3.9 (2H, m),4.6-4.8 (1H, m), 5.1-5.3 (3H, m), 5.3-5.4 (1H, m), 6.5-6.6 (1H, br),7.2-7.6 (8H, m)

[1029] Mass (APCI): 533 (M⁺+1)

Preparation 53-6

[1030](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-methoxymethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[1031]¹H-NMR (CDCl₃, δ): 1.4-2.1 (10H, m), 2.35 (3H, s), 3.2-3.5 (2H,m), 3.61 (3H, s), 3.6-3.9 (4H, m), 4.5-4.8 (2H, m), 5.21 (1H, d,J=15.6Hz), 7.1-7.6 (3H, m)

[1032] Mass (APCI): 399 (M⁺+1)

Preparation 54-1

[1033] To a solution of(3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1-[N-methyl-N-(2-pyridyl)amino]carbonylmethyl-1H-1,4-benzodiazepin-2-one(400 mg) in tetrahydrofuran (4 ml) was added cyclohexyl magnesiumchloride (1.08 ml) under stirring at 0° C. The mixture was stirred fortwenty minutes under the same conditions and at room temperatureovernight. Ethyl acetate and a saturated aqueous solution of ammoniumchloride were added to the reaction mixture. The separated organic layerwas washed with 0.1N aqueous hydrochloric acid, water, a saturatedaqueous sodium bicarbonate solution and brine successively and driedunder magnesium sulfate. The solvent was removed in vacuo to afford aresidue, which was subjected to column chromatography on silica geleluting with a mixture of toluene and ethyl acetate (20:1) to give(3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-1-cyclohexylcarbonylmcthyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one.

[1034]¹H-NMR (CDCl₃, δ): 1.1-2.0 (20H, m), 2.0-2.2 (1H, m), 2.31 (3H,s), 2.85 (1H, br, s), 3.81 (1H, d, J=17.0Hz), 4.88 (1H, d, J=17.0Hz),5.07-5.08 (2H, m), 5.19 (1H, d, J=9Hz), 6.42 (1H, d, J=9Hz), 7.1-7.5(8H, br, m)

[1035] Mass (APCI): 530 (M⁺+1)

Preparation 54-2

[1036](3RS)-3-Amino-5-cyclohexyl-1-cyclohexylcarbonylmethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[1037]¹H-NMR(CDCl₃, δ): 1.1-2.2 (10H, m), 2.31 (3H, s), 2.3-2.5 (1H, br,s), 3.82 (1H, d, J=16.9Hz), 4.35 (1H, s), 4.86 (1H, d, J=16.9Hz),7.2-7.5 (3H, m)

[1038] Mass (APCI): 396 (M⁺+1)

Preparation 55-1

[1039] 2-Chloroacetyl-6-methylaniline was prepared in a similar mannerto that of Preparation 50-1.

[1040] IR (Nujol, cm⁻¹): 3400, 3340, 1655, 1610, 1587, 1560, 1380, 788,738, 700

[1041]¹H-NMR (CDCl₃, δ): 2.17 (3H, s), 4.70 (2H, s), 6.2 (1H, br), 6.60(1H, t, J=7.2Hz), 7.22 (1H, d, J=7.2Hz), 7.53 (1H, d, J=7.2Hz)

[1042] APCI-MS (m/z): 184 (M⁺+1), 186 (M⁺+3)

Preparation 55-2

[1043] To a solution of 2-chloroacetyl-6-methylaniline (2.0 g) inmethylene chloride (20 ml) was added 1-methylpiperazine (2.29 g) understirring and cooling in an ice-bath. The mixture was stirred overnightat ambient temperature. Methylene chloride was removed in vacuo and tothe residue were added ethyl acetate and diluted aqueous solution ofsodium bicarbonate. From the aqueous layer the desired product wasextracted with ethyl acetate five times and combined organic extract waswashed with brine. After drying over magnesium sulfate, the solvent wasremoved in vacuo to give2-[(4-methylpiperazin-1-yl)acetyl]-6-methylaniline (2.07 g, 76.9% yield)as a crystalline mass.

[1044] IR (Nujol, cm⁻¹): 3380, 3280, 1654, 1610, 1588, 1562, 1375, 1280,1141, 1005, 974, 780, 740

[1045]¹H-NMR (CDCl₃, δ) :2.16 (3H, s), 2.31 (3H, s), 2.55 (4H, br, m),2.65 (4H, br, m), 3.79 (2H, s), 6.41 (1H, br, s), 6.57 (1H, t, J=7.3Hz),7.20 (1H, d, J=7.3Hz), 7.72 (1H, d, J=7.3Hz)

[1046] APCI-MS (m/z): 248 (M⁺+1)

Preparation 55-3

[1047](3RS)-3-Benzyloxycarbonylamino-5-(4-methylpiperazin-1-yl)methyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[1048]¹H-NMR (CDCl₃ , δ): 2.25 (3H, s), 2.35 (3H, s), 2.2-2.5 (8H, m),3.58 (2H, dd, J=13.7Hz, 45.9Hz), 5.10 (2H, s), 5.16 (1H, d, J=8.2Hz),6.56 (1H, d, J=8.2Hz), 7.1-7.73 (8H, m), 8.05 (1H, s)

[1049] APCI-MS (m/z): 436 (M⁺+1)

Preparation 55-4

[1050](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1,9-dimethyl-5-(4-methylpiperazin-1-yl)methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[1051] IR (Nujol, cm⁻¹): 1710, 1680

[1052]¹H-NMR(CDCl₃, δ): 2.27 (3H, s), 2.35 (3H, s), 3.17 (3H, s),2.4-2.6 (8H, m), 3.40 (1H, d, J=13.5Hz), 3.81 (1H, d, J=13.5Hz), 5.0-5.3(3H, br, m), 6.63 (1H, d, J=8.2Hz), 7.2-7.6 (8H, m)

[1053] Mass (APCI): 450 (M⁺+1)

Preparation 56-1

[1054] Dimethylamine aqueous solution (50%, 5.41 g) was added to asolution of 2-chloroacetyl-6-methylaniline (3.67 g) in methanol (50 ml)under stirring and cooling in an ice-bath. The mixture was stirred for 3hours at ambient temperature. Methanol was removed in vacuo to give aresidue, which was dissolved in ethyl acetate and washed with water.From the organic layer a basic subrtance was extracted with1N-hydrochloric acid twice. The aqueous extract was washed with ethylacetate and basidified with 1N-sodium hydroxide aqueous solution. Themixture was extracted with ethyl acetate twice and washed with water andbrine. The organic extract was dried over magnesium sulfate andevaporated in vacuo to afford an oil (2.58 g), which was pulverized in amixture of n-hexane and diisopropyl ether (1:1) and collected byfiltration to give 2-(N,N-dimethylamino)acetyl-6-methylaniline (2.03 g,52.8% yield) as a yellow crystalline powder.

[1055] IR (Nujol, cm⁻¹): 3410, 3300, 1640, 1612, 1585, 1552, 1378, 1008,983, 862, 770, 745

[1056]¹H-NMR (CDCl₃, δ): 2.16 (3H, s), 2.37 (6H, s), 3.71 (2H, s), 6.41(1H, br), 6.58 (1H, dd, J=7.2Hz, 8.1Hz) 7.18 (1H, d, J=7.2Hz), 7.71 (1H,d, J=7.2Hz)

[1057] APCI-MS (m/z): 193 (M⁺+1)

Preparation 56-2

[1058](3RS)-3-Benzyloxycarbonylamino-5-(N,N-dimethylamino)methyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[1059] mp: 204.1-205.2° C.

[1060] IR (Nujol, cm⁻¹): 3250 (sh), 3200, 1718, 1695, 1685, 1615, 1530,1391, 1370, 1058, 855, 785, 752, 690

[1061]¹H -NMR (CDCl₃, δ): 2.18 (6H, s), 2.34 (3H, s), 3.52 (2H, dd,J=13.7Hz, 101.6Hz), 5.11 (2H, s), 5.19 (1H, d, J=8.4Hz), 6.53 (1H, d,J=8.4Hz), 7.18-7.4 (7H, m), 7.58 (1H, d, J=7.8Hz), 8.07 (1H, s)

[1062] APCI-MS (m/z): 381 (M⁺+1)

Preparation 56-3

[1063](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl-5-(N,N-dimethylamino)methyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[1064] IR (Neat, cm⁻¹) 1750, 1720, 1675, 1620

[1065]¹H-NMR(CDCl₃, δ): 1.20 (3H, t, J=7.1Hz), 2.34 (3H, s), 2.35 (6H,s), 3.59 (2H, s), 3.82 (1H, d, J=16.9Hz), 4.09 (2H, q, J=7.1Hz), 4.76(1H, d, J=16.9Hz), 5.29 (1H, d, J=8.7Hz), 6.54 (1H, d, J=8.6Hz), 7.2-7.5(8H, m)

[1066] Mass (APCI): 467 (M⁺+1)

Preparation 56-4

[1067](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-9-methyl-5-(N,N-dimethylamino)methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to that ofPreparation 59-4.

[1068] IR (Nujol, cm⁻¹): 1715, 1685, 1600

[1069]¹H-NMR (DMSO-d₆, δ): 2.27 (3H, s), 2.31 (3H, s), 2.46 (3H, s),3.5-3.8 (3H, m), 3.42 (1H, d, J=16.5Hz), 4.98 (1H, d, J=9.6Hz), 5.01(2H, s), 7.1-7.4 (5H, m), 7.45 (1H, d, J=7.1Hz), 7.76 (1H, d, J=7.3Hz),8.07 (1H, d, J=8.6Hz), 8.31 (1H, s)

[1070] Mass (APCI): 439 (M⁺+1)

Preparation 56-5

[1071](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-9-methyl-5-(N,N-dimethylamino)-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[1072] IR (Neat, cm⁻¹): 1735, 1655, 1625

[1073]¹H-NMR(CDCl₃, δ): 1.5-1.9 (8H, m), 1.9-2.2 (2H, m), 2.22 (3H, s),2.34 (6H, s), 3.1-3.5 (4H, m), 3.6-3.8 (2H, m), 3.82 (1H, d, J=15.5Hz),4.97-5.31 (4H, m), 7.1-7.5 (7H, m), 7.7-7.9 (1H, m)

[1074] Mass (APCI): 546 (M⁺+1)

Preparation 56-6

[1075](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(N,N-dimethylamino)methyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[1076] IR (Neat, cm⁻¹): 3320, 1645

[1077]¹H-NMR(CDCl₃, δ): 1.2-2.6 (19H, m), 3.2-4.0 (6H, m), 4.13 (1H, m),4.47 (1H, m), 5.10 (1H, m), 7.25 (2H, m), 7.70 (1H, m)

[1078] Mass (APCI): 412 (M⁺+1)

Preparation 57-1

[1079] 2-(4-chlorobutanoyl)-6-methylaniline was prepared in a similarmanner to that of Preparation 50-1.

[1080]¹H-NMR (CDCl₃, δ): 2.16 (3H, s), 2.20 (2H, m), 3.15 (2H, t,J=7.0Hz), 3.66 (2H, t, J=6.3Hz), 6.38 (1H, br, s), 6.5-6.7 (1H, m),7.1-7.3 (1H, m), 7.6-7.8 (1H, m)

[1081] Mass (APCI): 212 (M⁺+1)

Preparation 57-2

[1082] A mixture of 2-(4-chlorobutanoyl)-6-methylaniline (538 mg) andpotassium t-butoxide (285 mg) in tetrahydrofuran (8 ml) was stirred atroom temperature for 1.5 hour. Ethyl acetate and 0.1N aqueoushydrochloric acid were added to the reaction mixture. The separatedorganic layer was washed with water, saturated aqueous sodiumbicarbonate and brine successively and dried over magnesium sulfate.Removal of the solvent in vacuo gave2-cyclopropylcarbonyl-6-methylaniline (445 mg, 100.0%) as a crystallinepowder.

[1083] IR (Nujol, cm⁻¹): 3450, 3300, 1610

[1084]¹H-NMR (CDCl₃, δ): 0.90-1.00 (2H, m), 1.14-1.21 (3H, m), 2.17 (3H,s), 2.5-2.8 (1H, m), 6.25 (2H, m), 6.64 (1H, t, J=7.2Hz), 7.22 (1H, t,J=7.2Hz), 7.88(1H, d, J=8.2Hz)

[1085] Mass (APCI): 176 (M⁺+1)

Preparation 57-3

[1086](3RS)-3-Benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[1087] IR (Nujol, cm⁻¹): 1715, 1675, 1620

[1088]¹H-NMR (DMSO-d₆, δ): 0.7-1.2 (4H, m), 2.03 (1H, m), 2.34 (3H, s),4.79 (1H, d, J=8.6Hz), 5.02 (2H, br, s), 7.1-7.5 (6H, m), 7.6-7.8 (1H,m), 7.9-8.2 (1H, m), 9.96 (1H, br, s)

[1089] Mass (APCI): 364 (M⁺+1)

Preparation 57-4

[1090](3RS)-3-Benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-1-ethoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[1091] IR (Neat, cm⁻¹): 1750, 1700, 1630

[1092]¹H-NMR (CDCl₃ , δ): 0.83-0.94 (2H, m), 0.98-1.10 (2H, m), 1.19(3H, t, J=7.1Hz), 1.9-2.4 (1H, m), 2.33 (3H, s), 3.80 (1H, d, J=16.8Hz),4.10 (2H, q, J=7.1Hz), 4.85 (1H, d, J=16.8Hz), 5.01-5.14 (2H, m), 5.18(1H, d, J=8.7Hz), 6.36 (1H, d, J=8.6Hz), 7.2-7.4 (7H, m), 7.63-7.68 (1H,m)

[1093] Mass (APCI): 450 (M⁺+1)

Preparation 57-5

[1094](3RS)-3-Benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-1-carboxymethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-4.

[1095] IR (Nujol, cm⁻¹): 1730, 1680, 1610 ¹H-NMR (CDCl₃, δ): 0.82-0.90(2H, m), 0.96-1.07 (2H, m), 1.26 (3H, t, J=7.1Hz), 1.90-2.04 (1H, m),2.31 (3H, s), 3.80 (1H, d, J=17.3Hz), 4.89 (1H, d, J=17.3Hz), 4.93-5.12(2H, m), 5.18 (1H, d, J=8.7Hz), 6.40 (1H, d, J=8.7Hz), 7.2-7.4 (7H, m),7.5-7.6 (1H, m)

[1096] Mass (APCI): 422 (M⁺+1)

Preparation 57-6

[1097](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[1098] IR (Nujol, cm⁻¹): 1725, 1675, 1650, 1615

[1099]¹H-NMR (CDCI₃, δ): 0.87-1.09 (4H, m), 1.25-1.73 (8H, m), 2.03-2.15(3H, m), 2.36 (3H, s), 3.31-3.80 (4H, m), 3.84 (1H, d, J=15.5Hz), 5.10(2H, m), 5.14 (1H, d, J=15.5Hz), 5.19 (1H, d, J=8.7Hz), 6.38 (1H, d,J=8.6Hz), 7.2-7.5 (7H, m), 7.6-7.7 (1H, m)

[1100] Mass (APCI): 529 (M⁺+1)

Preparation 57-7

[1101](3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[1102] IR (Nujol, cm⁻¹): 1675, 1645, 1600

[1103]¹H-NMR (CDCl₃, δ): 0.85-1.06 (4H, m), 1.4-1.8 (8H, m), 1.9-2.2(2H, m), 2.23 (1H, br, s), 2.37 (3H, s), 3.35-3.67 (4H, m), 3.86 (1H, d,J=15.5Hz), 4.34 (1H, s), 5.17 (1H, d, J=15.5Hz), 7.1-7.4 (2H, m),7.6-7.7 (1H, m)

[1104] Mass (APCI): 395 (M⁺+1)

Preparation 58-1

[1105] 2-methyl-6-isovalerylaniline was prepared in a similar manner tothat of Preparation 50-1.

[1106] IR (Nujol, cm⁻¹): 3475, 3330, 1638, 1610, 1580, 1555, 1025, 951,742

[1107]¹H-NMR (CDCl₃, δ): 0.99 (6H, d, J=6.6Hz), 2.17 (3H, s), 2.27 (1H,m), 2.81 (2H, d, J=6.9Hz), 6.4 (1H, br), 6.59 (1H, dd, J=7.3Hz,J=8.0Hz), 7.16-7.3 (2H, m), 7.66 (1H, d, J=8.0Hz)

[1108] APCI-MS (m/z): 192 (M⁺+1)

Preparation 58-2

[1109](3RS)-3-Benzyloxycarbonylamino-5-isobutyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 45-2.

[1110] mp: 208.4-209.1° C.

[1111] IR (Nujol, cm⁻¹): 3250 (sh), 3200, 1718, 1690 (sh), 1680, 1526,1390, 1367, 1057, 983, 761, 698

[1112]¹H-NMR (CDCl₃, δ): 0.75 (3H, d, J=6.6Hz), 0.86 (3H, d, J=6.6Hz),1.79 (1H, m), 2.36 (3H, s), 2.46 (1H, dd, J=9.4Hz, J=13.9Hz), 2.87 (1H,dd, J=3.9Hz, J=13.9Hz), 5.10 (2H, s), 5.15 (1H, d, J=8.4Hz), 6.48 (1H,d, J=8.4Hz), 7.12-7.45 (8H, m), 8.24 (1H, br, s)

[1113] APCI-MS (m/z): 380 (M⁺+1)

Preparation 58-3

[1114](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonylmethyl-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation of 59-3.

[1115] IR (Neat, cm⁻¹): 1750, 1720, 1620

[1116]¹H-NMR (CDCl₃, δ): 0.96 (6H, d, J=6.6Hz), 1.21 (3H, t, J=7.1Hz),2.13-2.28 (1H, m), 2.35 (3H, s), 2.57-2.88 (2H, m), 3.89 (1H, d,J=16.9Hz), 4.12 (2H, q, J=7.1Hz), 4.64 (1H, d, J=16.9Hz), 5.06 (1H, d,J=12.4Hz), 5.13 (1H, d, J=12.4Hz), 5.25 (1H, d, J=8.6Hz), 6.50 (1H, d,J=8.6Hz), 7.2-7.4 (8H, m)

[1117] Mass (APCI): 466 (M⁺+1)

Preparation 58-4

[1118](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-4.

[1119] IR (Nujol, cm⁻¹): 1715, 1680, 1610

[1120]¹H-NMR (CDCl₃, δ): 0.91 (3H, d, J=6.6Hz), 0.93 (3H, d, J=6.6Hz),2.1-2.2 (1H, m), 2.34 (3H, s), 2.55-2.73 (2H, m), 3.91 (1H, d,J=17.2Hz), 4.68 (1H, d, J=17.2Hz), 5.04 (1H, d, J=12.4Hz), 5.12 (1H, d,J=12.4Hz), 6.56 (1H, d, J=8.6Hz), 5.24 (1H, d, J=8.6Hz), 7.2-7.4 (8H, m)

[1121] Mass (APCI): 438 (M⁺+1)

Preparation 58-5

[1122](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-9-methyl-5-isobutyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[1123] IR (Nujol, cm⁻¹): 1710, 1675, 1650

[1124]¹H-NMR(CDCl₃, δ): 0.15 (6H, d, J=6.6Hz), 1.5-1.8 (8H, br), 1.9-2.2(2H, m), 2.2-2.3 (1H, m), 2.36 (3H, s), 2.58-2.95 (2H, m), 3.31-3.40(2H, m), 3.53-3.82 (2H, m), 3.91 (1H, d, J=15.7Hz), 4.95 (1H, d,J=15.7Hz), 5.05 (1H, d, J=12.4Hz), 5.12 (1H, d, J=12.4Hz), 5.27 (1H, d,J=8.6Hz), 6.51 (1H, d, J=8.6Hz), 7.1-7.5 (8H, m)

[1125] Mass (APCI): 545 (M⁺+1)

Preparation 58-6

[1126](3RS)-3-Amino-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-isobutyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-6.

[1127] IR (Nujol, cm^(−16l )) 3380, 1680, 1650

[1128]¹H-NMR(CDCl₃, δ): 0.98 (3H, d, J=6.5Hz), 0.99 (3H, d, J=6.5Hz),1.5-1.8 (8H, m), 1.9-2.1 (2H, m), 2.2-2.3 (1H, m), 2.36 (3H, s),2.56-2.68 (1H, m), 2.77-2.88 (1H, m), 3.35-3.44 (2H, m), 3.53-3.63 (1H,m), 3.77-3.85 (1H, m), 3.82 (1H, d, J=15.7Hz), 4.41(1H, s), 4.97 (1H, d,J=15.7Hz), 7.1-7.4 (3H, m)

[1129] Mass (APCI): 411 (M⁺+1)

Preparation 59-1

[1130] 2-Propanoyl-6-methylaniline was prepared in a similar manner tothat of Preparation 50-1.

[1131]¹H-NMR (CDCl₃, δ): 1.21 (3H, t, J=7.3Hz), 2.16 (3H, s), 2.98 (2H,q, J=7.3Hz), 6.40 (2H, m), 6.5-6.6 (1H, m), 7.18 (1H, d, J=7.1Hz), 7.66(1H, d, J=8.1Hz)

[1132] Mass (APCI): 164 (M⁺+1)

Preparation 59-2

[1133](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 50-2.

[1134] IR (Nujol, cm⁻¹) 1705, 1675, 1610

[1135]¹H-NMR (DMSO-d₆, δ): 0.99 (3H, t, J=7.4Hz), 2.34 (3H, s),2.65-2.90 (2H, m), 4.86 (1H, d, J=8.6Hz), 5.03 (2H, s), 7.1-7.5 (7H, m),7.58 (1H, d, J=7.9Hz), 8.09 (1H, d, J=8.6Hz), 9.95 (1H, s)

[1136] Mass (APCI): 352 (M⁺+1)

Preparation 59-3

[1137] A mixture of(3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one(1.0 g) and 60% sodium hydride (120 mg) in N,N-dimethylformamide wasstirred at 0° C. for 1 hour and at room temperature for 3 hours. To theresultant mixture was added dropwise ethyl bromoacetate (476 mg) undercooling at 0-5° C. in an ice-bath. The mixture was stirred for 5.5 hoursunder the same conditions. The reaction mixture was poured into 0.1Naqueous hydrochloric acid and extracted with ethyl acetate. The extractwas washed with water twice, saturated aqueous sodium bicarbonate andbrine successively and dried over magnesium sulfate. The solvent wasevaporated in vacuo to afford(3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-ethoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one(1.55 g) as an oil.

[1138] IR (Neat, cm⁻¹): 1750, 1720, 1622

[1139]¹H-NMR (CDCl₃, δ): 1.0-1.35 (6H, m), 2.33 (3H, s), 3.78 (1H, d,J=16.8Hz), 2.75-2.98 (2H, m), 4.85 (1H, d, J=16.8Hz), 4.10 (2H, q,J=7.1Hz), 5.06 (1H, d, J=12.3Hz), 5.13 (1H, d, J=12.3Hz), 5.27 (1H, d,J=8.7Hz), 6.49 (1H, d, J=8.6Hz), 7.2-7.4 (8H, m)

[1140] Mass (APCI): 438 (M⁺+1)

Preparation 59-4

[1141] A mixture of(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-1-ethoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one(1.55 g) and 1N sodium hydroxide (7.0 ml) in 1,2-dimethoxyethane (10 ml)was stirred at room temperature overnight. The reaction mixture wasevaporated in vacuo to afford a residue, which was dissolved in amixture of ethyl acetate and 1N aqueous hydrochloric acid. The separatedorganic layer was washed with water and brine, and then dried overmagnesium sulfate. The solvent was evaporated in vacuo to afford aresidue, which was triturated in diisopropyl ether and collected byfiltration to give(3RS)-3-benzyloxycarbonylamino-5-ethyl-1-carboxymethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one(1.22 g, 84.2% yield) as a white crystalline powder.

[1142] IR (Nujol, cm⁻¹): 1720, 1670, 1615

[1143]¹H-NMR (CDCl₃, δ): 1.14 (3H, t, J=7.4Hz), 2.31 (3H, s), 2.74-2.95(2H, m), 3.79 (1H, d, J=17.1Hz), 4.86 (1H, d, J=17.1Hz), 5.03 (1H, d,J=12.4Hz), 5.01 (1H, d, J=12.4Hz), 5.26 (1H, d, J=8.7Hz), 6.62 (1H, d,J=8.7Hz), 7.2-7.4 (8H, m). 7.87 (1H, br)

[1144] Mass (APCI): 410 (M⁺+1)

Preparation 59-5

[1145] A mixture of(3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-carboxymethyl-9-methyl-1H-1,4-benzodiazepin-2-one(1.22 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride(642 mg), 1-hydroxybenzotriazole (453 mg), 3-azabicyclo[3.2.2]nonane(419 mg) and triethylamine (1.55 ml) in N,N-dimethylformamide (30 ml)was stirred at room temperature overnight. Ethyl acetate and 0.1Naqueous hydrochloric acid were added to the reaction mixture, which wasstirred for several minutes. The separated organic layer was washed with1N aqueous hydrochloric acid, water twice, a saturated aqueous solutionof sodium bicarbonate and brine, successively, and then dried overmagnesium sulfate. The solvent was evaporated in vacuo, and the residuewas triturated in diisopropyl ether and collected by filtration toafford(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one(1.23 g, 79.9%) as a crystalline powder.

[1146] IR (Nujol, cm⁻¹): 1718, 1675, 1650

[1147]¹H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7.4Hz), 1.5-1.8 (10H, m), 2.34(3H, s), 2.90 (2H, q, J=7.4Hz), 3.29-3.36 (2H, m), 3.55-3.64 (1H, m),3.79 (1H, d, J=15.6Hz), 3.7-3.86 (1H, m), 5.05 (1H, d, J=12.4Hz), 5.12(1H, d, J=12.4Hz), 5.14 (1H, d, J=15.6Hz), 5.28 (1H, d, J=8.7Hz), 6.50(1H, d, J=8.7Hz), 7.2-7.4 (8H, m)

[1148] Mass (APCI): 517 (M⁺+1)

Preparation 59-6

[1149] A mixture of(3RS)-3-benzyloxycarbonylamino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one(1.23 g), 10% palladium on carbon (50% wet, 250 mg) and ammonium formate(600 mg) in ethanol (15 ml) was stirred at room temperature for 1 hour.The catalyst was filtered off and the filtrate was evaporated in vacuoto afford a residue, which was dissolved in ethyl acetate and washedwith saturated aqueous sodium bicarbonate, water and brine successively.After drying over sodium sulfate, the solvent was evaporated in vacuo toafford a residue, which was triturated in diisopropyl ether andcollected by filtration to give(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one(792 mg, 87.0% yield) as a crystalline powder.

[1150] IR (Nujol, cm⁻¹): 3360, 3370, 1680, 1655

[1151]¹H-NMR (CDCl₃, δ): 1.27 (3H, t, J=7.3Hz), 1.5-1.8 (8H, m), 1.8-2.1(2H, m), 2.35 (3H, s), 2.89 (2H, q, J=7.3Hz), 3.3-3.42 (2H, m), 3.5-3.6(2H, m), 3.79 (1H, d, J=15.5Hz), 4.41 (1H, s), 5.17 (1H, d, J=15.5Hz),7.1-7.4 (3H, m)

[1152] Mass (APCI): 383 (M⁺+1)

Preparation 60-1

[1153](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-3.

[1154] IR (Nujol, cm⁻¹): 1720, 1675

[1155]¹H-NMR (DMSO-d₆, δ): 0.97 (3H, t, J=7.1Hz), 2.39 (3H, s), 3.89(2H, q, J=7.1Hz), 4.21 (1H, d, J=16.7Hz), 4.68 (1H, d, J=16.7Hz), 5.05(1H, br, s), 5.20 (H, d, J=8.6Hz), 7.06 (1H, d, J=7.6Hz), 7.2-7.8 (11H,m), 8.4-8.6 (1H, m)

[1156] Mass (APCI): 504 (M⁺+1)

Preparation 60-2

[1157](3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1-carboxymethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Example 48-2.

[1158] IR (Nujol, cm⁻¹): 1720, 1680

[1159]¹H-NMR(CDCl₃, δ): 2.35 (3H, s), 3.88 (1H, d, J=17.2Hz), 4.84 (1H,d, J=17.2Hz), 5.0-5.3 (2H, m), 5.42 (1H, d, J=8.7Hz), 6.67 (1H, d,J=8.7Hz), 6.9-7.5 (11H, m), 7.6-7.8 (1H, m)

[1160] Mass (FAB): 476 (M⁺+1)

Preparation 61-1

[1161](3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-3.

[1162] IR (Nujol, cm⁻¹): 3350, 1710, 1670, 1620

[1163]¹H-NMR (CDCl₃, δ): 1.27 (3H, t, J=7.4Hz), 1.1-2.0 (10H, m),2.2-2.4 (1H, m), 2.32 (3H, s), 2.92 (2H, q, J=7.4Hz), 3.75 (1H, d,J=17Hz), 5.05 (1H, d, J=17Hz), 5.0-5.2 (2H, m), 5.25 (1H, d, J=8.7Hz),6.45 ((1H, d, J=8.6Hz), 7.1-7.5 (8H, m)

[1164] Mass (APCI)(e/z): 476 (M⁺+1)

Preparation 61-2

[1165](3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1166] IR (Neat, cm⁻¹): 3380, 3320, 1720, 1680

[1167]¹H-NMR (CDCl₃, δ): 1.29 (3H, t, J=7.1Hz), 1.1-1.4 (5H, m), 1.5-2.0(5H, m), 2.0-2.2 (2H, m), 2.2-2.4 (1H, m), 2.32 (3H, s), 2.8-3.0 (2H,m), 3.74(1H, d, J=17.0Hz), 4.39 (1H, t, J=1.5Hz), 5.06 (1H, d,J=17.0Hz), 7.1-7.4 (3H, m)

[1168] Mass (APCI)(e/z): 342 (M⁺+1)

Preparation 62-1

[1169](3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-3.

[1170] IR (Nujol, cm⁻¹): 3350, 1720, 1670, 1610

[1171]¹H-NMR(CDCl₃, δ): 1.19 (3H, d, J=7.1Hz), 1.33 (3H, d, J=6.6Hz),1.1-2.0 (10H, m), 2.32 (3H, s), 2.2-2.4 (1H, m), 3.1-3.3 (1H,m), 3.79(1H, d, J=17.0Hz), 4.93 (1H, d, J=17.0Hz), 5.05 (1H, d, J=12.6Hz)(5.12,d, J=12.6Hz), 5.20 (1H, d, J=8.7Hz), 6.42 (1H, d, J=8.6Hz), 7.1-7.5 (8H,m)

[1172] Mass (APCI)(e/z): 490 (M⁺+1)

Preparation 62-2

[1173](3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1174] IR (Neat, cm⁻¹): 3380, 3320, 1725, 1680, 1620

[1175]¹H-NMR (CDCl₃, δ): 1.21 (3H, d, J=7.0Hz), 1.35 (3H, d, J=6.6Hz),1.1-1.5 (5H, m), 1.5-2.2 (5H, m), 2.2-2.4 (1H, m), 2.35 (3H, s), 3.1-3.3(1H, m), 3.80(1H, d, J=17.0Hz), 4.34 (1H, s), 4.92 (1H, d J=17.0Hz),7.1-7.4 (3H, m)

[1176] Mass (APCI)(e/z): 356 (M⁺+1)

Preparation 63-1

[1177](3RS)-3-Benzyloxycarbonylamino-1-cycloheptylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 54-1.

[1178] IR (Nujol, cm⁻¹): 3400, 1720, 1670, 1620

[1179] Mass (APCI)(e/z): 476 (M⁺+1)

[1180]¹H-NMR(CDCl₃, δ): 1.3-2.0 (12H, m), 2.32 (3H, s), 2.4-2.6 (1H, m),2.61 (3H,s), 3.75 (1H, d, J=17Hz), 5.10 (1H, d, J=17Hz), 5.0-5.2 (2H,m), 5.24 (1H, d, J=8.7Hz), 6.48 (1H, d, J=8.7Hz), 7.1-7.5 (8H, m)

Preparation 63-2

[1181](3RS)-3-Amino-1-cycloheptylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1182] IR (Nujol, cm⁻¹): 3360, 3320, 1720, 1670, 1620

[1183]¹H-NMR (CDCl₃, δ): 1.3-2.3 (12H, br), 2.32 (3H, s), 2.4-2.6 (1H,m), 2.60 (3H, s), 3.74 (1H, d, J=17Hz), 4.39 (1H, s), 5.12 (1H, d,J=17Hz), 7.1-7.5 (3H, m)

[1184] Mass (APCI)(e/z): 342 (M⁺+1)

Preparation 64-1

[1185](3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-3.

[1186] IR (Nujol, cm⁻¹): 3300, 1715, 1665, 1605

[1187]¹H-NMR (CDCl₃, δ): 0.8-1.5 (10H, m), 1.5-1.9 (4H, m), 2.0-2.2 (1H,m), 2.2-2.4 (1H, m), 2.32 (3H, s), 3.78 (1H, d, J=17.0Hz), 5.01 (1H, d,J=17.0Hz), 5.0-5.2 (2H, m), 5.17 (1H, d, J=9Hz), 6.33 (1H, d, J=9Hz),7.1-7.4 (7H, m), 7.6-7.7 (1H, m)

[1188] Mass (APCI)(e/z): 488 (M⁺+1)

Preparation 64-2

[1189](3RS)-3-Amino-1-cyclohexylcarbonylmethyl-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1190] IR (Nujol, cm⁻¹): 3400, 3310, 1720, 1680, 1610

[1191]¹H-NMR (CDCl₃, δ): 0.8-2.4 (16H, m), 2.32 (3H, s), 2.2-2.4 (1H,br), 2.7-2.9 (1H, m), 3.88 (1H, d, J=17Hz), 4.32 (1H, s), 5.01 (1H, d,J=17Hz), 7.1-7.4 (3H, m)

[1192] Mass (APCI)(e/z): 356 (M⁺+1)

Preparation 65-1

[1193](3RS)-3-Benzyloxycarbonylamino-1-cyclopentylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 54-1.

[1194] Mass (APCI)(e/z): 448 (M⁺+1)

Preparation 65-2

[1195](3RS)-3-Amino-1-cyclopentylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

Preparation 66-1

[1196](3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-5.

[1197] IR (Nujol, cm⁻¹): 3380, 1700, 1670, 1640

[1198]¹H-NMR (CDCl₃, δ): 1.25 (3H, t, J=7.3Hz), 1.3-1.9 (10H, m), 2.34(3H, s), 2.8-3.0 (2H, m), 3.2-3.5 (4H, m), 3.71(1H, d, J=15.4Hz),5.0-5.2 (3H, m), 5.27 (1H, d, J=8.7Hz), 6.50 (1H, d, J=8.7Hz), 7.1-7.4(8H, m)

[1199] Mass (APCI)(e/z): 505 (M⁺+1)

Preparation 66-2

[1200](3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1201] IR (Nujol, cm⁻¹): 3380, 3270, 1670, 1640

[1202]¹H-NMR (CDCl₃, δ): 1.27 (3H, t, J=7.3Hz), 1.3-2.0 (10H, br), 2.26(2H, br), 2.34 (3H,s), 2.8-3.0 (2H, m), 3.2-3.6 (4H, m), 3.70 (1H, d,J=15.3Hz), 4.41 (1H, s), 5.07 (1H, d, J=15.3Hz), 7.1-7.4 (3H, m)

[1203] Mass (APCI)(e/z): 371 (M⁺+1)

Preparation 67-1

[1204](3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-5.

[1205] IR (Nujol, cm⁻¹): 3370, 1710, 1670, 1645

[1206]¹H-NMR (CDCl₃, δ): 1.22 (3H, d, J=7.0Hz), 1.33 (3H, d, J=6.6Hz),1.3-1.9 (10H, m), 2.35 (3H, s), 3.1-3.6 (5H, m), 3.76 (1H, d, J=15.3Hz),4.96 (1H, d, J=15.3Hz), 5.0-5.2 (2H, m), 5.22 (1H, d J=9Hz), 6.48 (1H,d, J=9Hz), 7.1-7.5 (8H, m)

[1207] Mass (APCI)(e/z): 519 (M⁺+1)

Preparation 67-2

[1208](3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1209] IR (Nujol, cm⁻¹): 3350, 3280, 1675, 1640

[1210]¹H-NMR (CDCl₃, δ): 1.22 (3H, d, J=7.0Hz), 1.34 (3H, d, J=6.6Hz),1.3-1.9 (10H, m), 2.23 (2H, br, s), 2.35 (3H, s), 3.1-3.6 (5H, m), 3.77(1H, d, J=15.2Hz), 4.36 (1H, s), 4.96 (1H, d, J=15.2Hz), 7.1-7.4 (3H, m)

[1211] Mass (APCI)(e/z): 385 (M⁺+1)

Preparation 68-1

[1212](3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-5.

[1213] IR (Nujol, cm⁻¹): 3370, 1705, 1660, 1640

[1214]¹H-NMR (CDCl₃,δ): 0.8-1.1 (4H,m), 1.2-1.9 (10H, m), 2.0-2.2 (1H,m), 2.35 (3H, s), 3.3-3.5 (4H, m), 3.74 (1H, d, J=15.3Hz), 5.02 (1H,d,J=15.3Hz), 5.0-5.2 (2H, m), 5.19 (1H, d, J=9Hz), 6.37 (1H, d, J=9Hz),7.2-7.4 (7H, m), 7.6-7.7 (1H, m)

[1215] Mass (APCI)(e/z): 517 (M⁺+1)

Preparation 68-2

[1216](3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1217] IR (Nujol, cm⁻¹): 3780, 3280, 1675, 1650

[1218]¹H-NMR (CDCl₃, δ): 0.8-1.1 (4H, m), 1.2-1.9 (10H, m), 1.9-2.2 (3H,m), 2.35 (3H, s), 3.2-3.6 (4H, m), 3.74 (1H, d, J=15.2Hz), 3.97 (1H, s),5.04 (1H, d, J=15.2Hz), 7.1-7.4 (2H, m), 7.4-7.5 (1H, m)

[1219] Mass (APCI)(e/z): 383 (M⁺+1)

Preparation 69-1

[1220](3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylamino-2,3-dihydro-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-5.

[1221] IR (Nujol, cm⁻¹): 3400, 1710, 1670, 1640

[1222]¹H-NMR (CDCl₃, δ): 0.98 (6H, d, J=6.6Hz), 1.4-1.9 (10H, m),2.2-2.4 (1H, m), 2.36 (3H, s), 2.5-3.0 (2H, m), 3.3-3.5 (4H, m),3.81(1H, d, J=5.5Hz), 4.89 (1H, d, J=15.5Hz), 5.0-5.2 (2H, m), 5.25 (1H,d, 9Hz), 6.50 (1H, d, J=9Hz), 7.1-7.5 (8H, m)

[1223] Mass (APCI)(e/z): 533 (M⁺+1)

Preparation 69-2

[1224](3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1225] mp. 138.1-140.2° C.

[1226] IR (Nujol, cm⁻¹): 3370, 3300, 1675, 1635

[1227]¹H-NMR (CDCl₃, δ): 0.98 (6H, d, J=6.6Hz), 1.4-1.9 (10H, m),2.1-2.3 (3H, m), 2.36 (3H, s), 2.5-2.9 (2H, m), 3.3-3.5 (4H, m), 3.81(1H, d, J=15.4Hz), 4.40 (1H, s), 4.89 (1H, d, J=15.4Hz), 7.1-7.4 (3H, m)

[1228] Mass (APCI)(e/z): 399 (M⁺+1)

Preparation 70-1

[1229](3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-5.

[1230] IR (Nujol, cm⁻¹): 3380, 1710, 1670, 1645

[1231]¹H-NMR (CDCl₃, δ): 1.1-2.2 (20H, m), 2.35 (3H, s), 2.7-3.0 (1H,m), 3.2-3.6 (4H, m), 3.78 (1H, d, J=15.3Hz), 4.91 (1H, d J=15.3Hz),5.0-5.2 (2H, m), 5.21 (1H, d, J=8.6Hz), 6.49 (1H, d, J=8.6Hz), 7.1-7.5(8H, m)

[1232] Mass (APCI)(e/z): 559 (M⁺+1)

Preparation 70-2

[1233](3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1234] mp. 174.1-175.6° C.

[1235] IR (Nujol, cm⁻¹): 3350, 3280, 1670, 1635

[1236]¹H-NMR (CDCl₃, δ): 1.2-2.1 (20H, m), 2.35 (3H, s), 2.7-2.9 (1H,m), 3.2-3.6 (4H, m), 3.79 (1H, d, J=15.2Hz), 4.69 (1H, s), 4.92 (1H, d,J=15.2Hz), 7.1-7.4 (3H, m)

[1237] Mass (APCI)(e/z): 425 (M⁺+1)

Preparation 71

[1238]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-4-oxide-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Preparation 32.

[1239] mp. 253.6-255.4° C.

[1240] IR (Nujol, cm⁻¹): 3340, 1692, 1640

[1241]¹H-NMR (DMSO-d₆, δ): 1.2-1.9 (10H, m), 2.23 (3H, s), 2.38 (3H, s),2.41 (3H, s), 2.9-3.6 (4H, m), 4.07 (1H, d, J=16Hz), 4.99 (1H, d,J=16Hz), 5.70 (1H, d, J=9.5Hz), 6.7-6.8 (1H, m), 7.0-7.6 (7H, m), 9.26(1H, s)

[1242] Mass (APCI)(e/z): 506 (M⁺+1)

Preparation 72-1

[1243](3RS)-3-Benzyloxycarbonylamino-1-cyclooctylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 54-1.

[1244] IR (Neat, cm⁻¹): 3400, 1730, 1690, 1670

[1245]¹H-NMR (CDCl₃, δ): 1.3-2.0 (14H, m), 2.33 (3H, s), 2.61 (3H, s),2.4-2.6 (1H, m), 3.75 (1H, d, J=17Hz), 5.10 (1H, d, J=17Hz), 5.0-5.2(2H, m), 5.24 (1H, m), 6.48 (1H, d, J=8.7Hz), 7.1-7.5 (8H, m

[1246] Mass (APCI)(e/z): 490 (M⁺+1)

Preparation 72-2

[1247](3RS)-3-Amino-1-cyclooctylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1248] IR (Neat, cm⁻¹): 3400, 3300, 1725, 1690, 1660

[1249]¹H-NMR (CDCl₂, δ): 1.3-2.0 (14H, m), 2.16 (2H, s), 2.33 (3H, s),2.4-2.6 (1H, m), 2.60 (3H, s), 3.74 (1H, d, J=17Hz), 4.39 (1H, m), 5.12(1H, d, J=17Hz), 7.1-7.5 (3H, m)

[1250] Mass (APCI)(e/z): 356 (M⁺+1)

Preparation 73-1

[1251](3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-3.

[1252] IR (Nujol, cm⁻¹): 3300, 1710, 1665

[1253]¹H-NMR (CDCl₃, δ): 0.97 (6H, d, J=6.6Hz), 1.1-2.0 (10H, m),2.1-2.3 (2H, m), 2.31 (3H, s), 2.5-3.0 (2H, m), 3.90 (1H, d, J=17.3Hz),4.83 (1H, d, J=17.3Hz), 5.0-5.2 (2H, m), 5.23 (1H, d, J=8.7Hz), 6.46(1H, d, J=8.5Hz), 7.1-7.5 (8H, m)

[1254] Mass (APCI)(e/z): 504 (M⁺+1)

Preparation 73-2

[1255](3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 59-6.

[1256] IR (Neat, cm⁻¹): 3380, 3320, 1720, 1680, 1620

[1257]¹H-NMR (CDCl₃, δ): 0.98 (6H, d, J=6.6Hz), 1.1-2.0 (10H, m),2.0-2.4 (4H, m), 2.31 (3H, s), 2.5-2.9 (2H, m), 3.90 (1H, d, J=17Hz),3.38 (1H, m), 4.83 (1H, d, J=17Hz), 7.1-7.4 (3H, m)

[1258] Mass (APCI)(e/z): 370 (M⁺+1)

Preparation 74-1

[1259](3RS)-1-Cyclohexylcarbonylmethyl-3-[N-t-butoxycarbonyl-(S)-phenylalanyl]amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas obtained by reacting(3RS)-1-cyclohexylcarbonylmethyl-3-amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewith N-t-butoxycarbonyl-(S)-phenylalanine in a similar manner to that ofPreparation 59-5.

[1260]¹H-NMR (CDCl₃, δ): 1.15-1.35 (9H, m), 1.37 (9H, s), 1.6-1.85 (4H,m), 1.85-2.0 (1H, m), 2.2-2.4 (1H, m), 2.34 (3H, s),2.85-3.1 (2H, m),3.14-3.29 (1H, m), 3.75 (1H, d, J=17.2Hz), 4.50 (1H, br, s), 4.94 (1H,br, d), 5.06 (1H, d, J=17.2Hz), 5.39-5.46 (1H, m), 7.19-7.5 (8H, m),7.61 (1H, br, d)

[1261] APCI-MS (m/z)=589 (M⁺+1)

Preparation 74-2

[1262] A mixture of(3RS)-1-cyclohexylcarbonylmethyl-3-[N-t-butoxy-carbonyl-(S)-phenylalanyl]amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(47.70 g, 81.02 mmol) and 4N-solution of hydrogen chloride in ethylacetate (800 ml) was stirred for 0.5 hour under cooling in an ice-bathand stirred for 3 hours at ambient temperature. After removal ofhydrogen chloride as completely as possible by babbling of nitrogen gas,the solution was washed with a dilute aqueous solution of sodiumbicarbonate twice and with water. After drying over magnesium sulfate,the solvent was evaporated in vacuo to give an oily mixture ofdiastereoisomers (35.51 g), which was separated by medium pressureliquid chromatography on silica gel eluting with a mixture of chloroformand methanol (20:1). The fractions containing the following A-isomer andB-isomer were collected and evaporated in vacuo to afford amorphousmasses of pure A-isomer (11.81 g) and B-isomer (14.30 g) respectively.

[1263] A-isomer:(3R)-1-cyclohexylcarbonylmethyl-3-[(S)-phenylalanyl]amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[1264]¹H-NMR (CDCl₃, δ): 1.05-1.45 (5H, m), 1.28 (3H, t, J=7.4Hz), 1.60(2H, s), 1.6-2.0 (5H, m), 2.25-2.43 (1H, m), 2.35 (3H, s), 2.60 (1H, dd,J=10.5Hz, J=13.7Hz), 2.93 (2H, q, J=7.4Hz), 3.34 (1H, dd, J=3.5Hz,J=13.7Hz), 3.66 (1H, dd, J=3.5Hz, J=10.5Hz), 3.75 (1H, d, J=17.1Hz),5.08 (1H, d, J=17.1Hz), 5.48 (1H, d, J=8.5Hz), 7.15-7.45 (8H, m), 8.77(1H, d, J=8.5Hz)

[1265] APCI-MS (m/z)=489 (M⁺+1)

[1266] B-isomer:(3S)-1-cyclohexylcarbonylmethyl-3-[(S)-phenylalanyl]amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

[1267]¹H-NMR (CDCl₃, δ): 1.05-1.45 (5H, m), 1.28 (3H, t, J=7.4Hz), 1.63(2H, s), 1.6-2.0 (5H, m), 2.25-2.43 (1H, m), 2.34 (3H, s), 2.70 (1H, dd,J=10.5Hz, J=13.7Hz), 2.94 (2H, q, J=7.4Hz), 3.31 (1H, dd, J=3.8Hz,J=10.1Hz), 3.64 (1H, dd, J=3.8Hz, J=10.1Hz), 3.74 (1H, d, J=17.1Hz),5.06 (1H, d, J=17.1Hz), 5.46 (1H, d, J=8.5Hz), 7.15-7.45 (8H, m), 8.73(1H, d, J=8.5Hz)

[1268] APCI-MS (m/z)=489 (M⁺+1)

Preparation 74-3(1)

[1269] A mixture of(3S)-1-cyclohexylcarbonylmethyl-3-[(S)-phenylalanyl]-amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(14.30 g) and phenyl isothiocyanate (4.35 g) in methylene chloride (250ml) was heated under stirring with vaporizing spontaneously. Thisvaporizing procedure was repeated three times. The resultant reactionmixture was evaporated in vacuo to remove methylene chloride completely.To the oil obtained above was added trifluoroacetic acid (200 ml) andthe mixture was heated under stirring at 50° C. for 20 minutes. Themixture was evaporated in vacuo. The resultant residue was subjected tocolumn chromatography on silica gel eluting with a mixture of chloroformand methanol (20:1). The fractions containing the desired product werecombined and evaporated in vacuo to give an oily product, which wasdissolved in ethyl acetate and washed with a diluted aqueous sodiumbicarbonate. After drying over magnesium sulfate, the organic extractwas concentrated in vacuo to afford(3S)-3-amino-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(6.30 g, 63.1%) as an amorphous mass.

[1270]¹H-NMR (CDCl₃, δ): 1.05-1.4 (5H, m), 1.26 (3H, t, J=7.1Hz),1.55-1.95 (5H, m), 2.25-2.45 (1H, m), 2.32 (3H, s), 2.90 (2H, q,J=7.1Hz), 2.96 (2H, br, s), 3.75 (1H, d, J=17.1Hz), 4.46 (1H, s), 5.07(1H, d, J=17.1Hz), 7.15-7.4 (3H, m)

[1271] APCI-MS (m/z)=342 (M⁺+1)

[1272] [α]_(D) ^(29.2)=−6.59° (C=1.41, CHCl₃)

Preparation 74-3(2)

[1273](3R)-3-Amino-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas obtained in a similar manner to that of Preparation 74-3(1).

[1274]¹H-NMR (CDCl₃, δ): 1.05-1.4 (5H, m), 1.26 (3H, t, J=7.1Hz),1.55-1.95 (5H, m), 2.25-2.45 (1H, m), 2.32 (3H, s), 2.90 (2H, q,J=7.1Hz), 3.47 (2H, br, s), 3.75 (1H, d, J=17.1Hz), 4.48 (1H, s), 5.07(1H, d, J=17.1Hz), 7.15-7.4 (3H, m)

[1275] APCI-MS (m/z): 342 (M⁺+1)

[1276] [α]_(D) ^(30.4)=5.78° (C=1.21, CHCl₃)

EXAMPLE 1(1)

[1277] To a solution of(3RS)-3-amino-1-[3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.200 g) in dry methylene chloride (10 ml) was added dropwise asolution of 3-methoxyphenyl isocyanate (0.086 g) in dry methylenechloride (5 ml) at 5˜10° C. in an ice-bath. The mixture was allowed towarm to room temperature and stirred overnight.

[1278] The reaction mixture was washed with a saturated aqueous sodiumhydrogen carbonate (10 ml) and a brine (10 ml). The organic layer wasdried over anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was subjected by column chromatography on silica gel with amixture of chloroform and methanol (10:1) as an eluent to affordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methoxyphenyl)urea(0.270 g).

[1279] mp: 139-142° C.

[1280] IR(KBr): 3350, 2933, 2864, 1659, 1601, 1548, 1492, 1428, 1201,762 cm⁻¹

[1281]¹H-NMR (CDCl₃, δ): 1.02 (3H, d, J=7.2Hz), 1.29 (3H, d, J=7.2Hz),1.55-1.80 (8H, m), 2.02-2.10 (2H, m), 3.15-3.24 (1H, m), 3.44-3.80 (4H,m), 4.42 (1H, d, J=17.2Hz), 4.89 (1H, d, J=17.2Hz), 5.50 (1H, d,J=8.0Hz), 6.55 (1H, d, J=8.4Hz), 6.81 (1H, d, J=8.4Hz), 6.90 (1H, d,J=8.4Hz), 7.07-7.32 (8H, m), 7.47 (1H, t, J=7.2Hz), 7.57 (1H, d,J=7.2Hz)

[1282] Mass: m/e=532 (M⁺+1)

EXAMPLE 1(2)

[1283] The following compound was prepared in a similar manner to thatof Example 1(1).

[1284]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylthiophenyl)urea

[1285] mp: 134-135° C.

[1286] IR(KBr): 3350, 2931, 1659, 1541, 1451, 1201, 766 cm⁻¹

[1287]¹H-NMR (CDCl₃, δ): 0.99 (3H, d, J=6.8Hz), 1.29 (3H, d, J=6.8Hz),1.50-1.90 (8H, m), 2.00-2.10 (2H, m), 2.41 (3H, s), 3.10-3.22 (1H, m),3.40-3.84 (4H, m), 4.41 (1H, d, J=16.0Hz), 4.91 (1H, d, J=16.0Hz), 5.48(1H, d, J=7.6Hz), 6.85-7.31 (7H, m), 7.37 (1H, s), 7.46 (1H, t,J=7.2Hz), 7.55 (1H, t, J=7.2Hz)

[1288] Mass: m/e=548 (M⁺+1)

EXAMPLE 1(3)

[1289] The following compound was prepared in a similar manner to thatof Example 1(1).

[1290]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-phenylurea

[1291] mp: 132-135° C.

[1292] IR(KBr): 3362, 2932, 1657, 1598, 1546, 1496, 1449, 1201, 756 cm⁻¹

[1293]¹H-NMR (CDCl₃, δ): 0.99 (3H, d, J=6.8Hz), 1.28 (3H, d, J=6.8Hz),1.50-1.90 (8H, m), 1.90-2.10 (2H, m), 3.10-3.20 (1H, m), 3.13-3.75 (4H,m), 4.43 (1H, d, J=16.0Hz), 4.76 (1H, d, J=16.0Hz), 5.48 (1H, d,J=8.0Hz), 6.90-7.53 (11H, m)

[1294] Mass: m/e=502 (M⁺+1)

EXAMPLE 1(4)

[1295] The following compound was prepared in a similar manner to thatof Example 1(1).

[1296]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-cyclohexylurea

[1297] mp: 138-140° C.

[1298] IR(KBr): 3373, 2930, 2861, 1658, 1546, 1451, 1201, 762 cm⁻¹

[1299]¹H-NMR (CDCl₃, δ): 0.98 (3H, d, J=6.8Hz), 1.00-1.20 (6H, m), 1.28(3H, d, J=6.8Hz), 1.40-2.10 (14H, m), 3.10-3.20 (1H, m), 3.40-3.84 (2H,m), 4.37 (1H, d, J=16.4Hz), 4.54 (1H, d, J=7.2Hz), 4.86 (1H, d,J=16.4Hz), 5.40 (1H, d, J=7.6Hz), 6.17 (1H,d, J=7.6Hz), 7.20-7.60 (4H,m)

[1300] Mass m/e=508 (M⁺+1)

EXAMPLE 2

[1301] To a solution of(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.230 g) in dry tetrahydrofuran (20 ml) was added dropwise a solutionof 3-methylphenyl isocyanate (0.095 g) in dry tetrahydrofuran (5 ml) at5˜10° C. in an ice-bath for 10 minutes. The mixture was allowed to warmto room temperature and stirred at ambient temperature for 3 hours. Theresultant mixture was concentrated in vacuo and the residue wassubjected by column chromatography on silica gel with a mixture ofchloroform and ethyl acetate (10:1). The fractions containing thedesired compound were combined and evaporated in vacuo to affordN-[(3RS)-1-(2-acetylthiophen-3-yl)methyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(0.210 g).

[1302] mp: 219-221° C. (dec.)

[1303] IR(KBr): 3324, 2968, 2926, 1661, 1649, 1559, 1491, 1415, 1381,1247, 1165, 774, 692 cm⁻¹

[1304]¹H-NMR (CDCl₃, δ): 0.89 (3H, d, J=6.8Hz), 1.29 (3H, d, J=6.8Hz),2.26(3H, s), 2.49(3H, s), 3.10-3.20 (1H, m), 5.32(1H, d, J=17.2Hz), 5.50(1H, d, J=8.0Hz), 5.68 (1H, d, J=17.2Hz), 6.80-7.55 (12H, m)

[1305] Mass: m/e=489 (M⁺+1)

EXAMPLE 3

[1306] To a suspension of sodium hydride (0.030 g of a 65% dispersion inmineral oil) in dry N,N-dimethylformamide (5 ml) was added graduallyN-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(0.250 g) at 5˜10° C. in an ice-bath for 30 minutes. The mixture wasstirred at the same temperature for 1 hour and then at room temperaturefor 2 hours. To the above mixture was added dropwise a solution ofN-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.200 g) in dry N,N-dimethylformamide (5 ml) for 10 minutes and stirred at ambienttemperature overnight. The reaction mixture was concentrated in vacuoand the residue was taken up with ethyl acetate (100 ml) and a saturatedaqueous sodium hydrogen carbonate (50 ml). The organic layer wasseparated, washed with a brine (50 ml), dried over anhydrous magnesiumsulfate and evaporated in vacuo to give a crude product. The product waspurified by column chromatography on silica gel with a mixture ofchloroform and ethyl acetate (10:1) as an eluent. The fractionscontaining the desired compound were combined and evaporated in vacuo toaffordN-[(3RS)-1-(3-azabicycio[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(0.160 g).

[1307] mp: 123-126° C.

[1308] IR(KBr): 3364, 2929, 2862, 1660, 1616, 1554, 1451, 1201 cm⁻¹

[1309]¹H-NMR (CDCl₃, δ): 0.99 (3H, d, J=7.2Hz), 1.29 (3H, d, J=7.2Hz),1.50-1.80 (8H, m), 2.00-2.10 (2H, m), 2.28 (3H, s), 3.10-3.22 (1H, m),3.42-3.82 (4H, m), 4.42 (1H, d, J=17.2Hz), 4.87 (1H, d, J=17.2Hz), 5.47(1H, d, J=8.0Hz), 6.72 (1H, d, J=8.4Hz), 6.81 (1H, d, J=7.4Hz),7.07-7.56 (8H, m)

[1310] Mass: m/e=516 (M⁺+1)

EXAMPLE 4

[1311] To a solution of(3RS)-3-amino-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.165 g) in N,N-dimethylformamide (5 ml) was added gradually4-nitrophenyl N-(3-acetylphenyl)carbonate (0.155 g) and then dropwisetriethylamime (0.087 g) at 5˜10° C. in an ice-bath and the mixture wasstirred at ambient temperature overnight. The resultant mixture wasconcentrated in vacuo. The residue was taken up with ethyl acetate (100ml) and a saturated aqueous sodium hydrogen carbonate (50 ml) and washedwith a brine (50 ml). Dryness over anhydrous magnesium sulfate andevaporation gave a crude product. The crude product was purified bycolumn chromatography on silica gel with a mixture of chloroform andmethanol (50:1) as an eluent to affordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-acetylphenyl)urea(0.190 g).

[1312] mp: 138-140° C.

[1313] IR(KBr): 3363, 2933, 2865, 1682, 1661, 1550, 1488, 1217, 1202cm⁻¹

[1314]¹H-NMR (CDCl₃, δ): 0.99 (3H, d, J=7.2Hz), 1.29 (3H, d, J=7.2Hz),1.56-1.80 (8H, m), 2.00-2.16 (2H, m), 2.49 (3H, s), 3.14-3.22 (1H, m),3.44-3.84 (4H, m), 4.49 (1H, d, J=16.0Hz), 4.98 (1H, d, J−16.0Hz), 5.51(1H, d, J=7.6Hz), 7.10-7.64 (9H, m), 7.93 (1H, s)

[1315] Mass: m/e=534 (M⁺+1)

EXAMPLE 5

[1316] To a solution of(3RS)-3-amino-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one(0.170 g) in dry tetrahydrofuran was added gradually 4-nitrophenylN-[3-(tetrazol-5-yl)phenyl]carbamate (0.152 g) and then dropwise asolution of triethylamime (0.090 g) in tetrahydrofuran (5 ml) at roomtemperature. The mixture was stirred at ambient temperature overnight.The mixture was concentrated in vacuo and the residue was subjected bycolumn chromatography on silica gel with a mixture of chloroform andmethanol (100:1) as an eluent to affordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(0.150 g).

[1317] mp: 220° C. (dec.)

[1318] IR(KBr): 3347, 2933, 2866, 1655, 1584, 1452, 1273, 1204, 758 cm⁻¹

[1319]¹H-NMR (DMSO-d₆, δ): 0.91 (3H, d, J=7.2Hz), 1.29 (3H, d, J=7.2Hz),1.40-1.80 (8H, m), 1.90-2.10 (2H, m), 3.20-3.30 (1H, m), 3.30-3.80 (4H,m), 4.64 (1H, d, J=16.8Hz), 4.93 (1H, d, J=16.8Hz), 5.17 (1H, d,J=8.4Hz), 7.28-7.60 (9H, m), 7.99 (1H, s) 9.14 (1H, s)

[1320] Mass: m/e=558 (M⁺+1)

EXAMPLE 6(1)

[1321] To a suspension of sodium hydride (0.027 g of a 64% dispersion inmineral oil) in N,N-dimethylformamide (3 ml) was added graduallyN-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(0.200 g) at ambient temperature and the mixture was stirred for 1 hourunder the same conditions. To the mixture was added sodium iodide (0.107g) and followed dropwise a solution of 2-chloromethyl-3-methylpridine(0.093 g) in N,N-dimethylformamide (2 ml) at the same temperature. Theresultant mixture was concentrated in vacuo and the residue was taken upwith ethyl acetate and water. The aqueous layer was extracted withanother ethyl acetate. The combined organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to give a crude compound.The crude compound was recrystallized with isopropyl ether andchloroform to giveN-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-1-(3-methylpyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(0.23 g) as a colorless powder.

[1322] mp: 185-187° C.

[1323] IR(KBr): 2956, 1695, 1649, 1614, 1564, 1492, 1447, 1384, 1214,778 cm⁻¹

[1324]¹H-NMR (DMSO-d₆, δ): 0.79 (3H, d, J=8Hz), 0.87 (3H, d, J=8Hz),1.82-1.88 (1H, m), 2.24 (3H, s), 2.35 (3H, s), 2.46 (1H, dd, J=16Hz,J=16Hz), 2.86 (1H, dd, J=8Hz, J=16Hz), 5.15 (2H, q, J=18Hz), 5.20 (1H,s), 6.73 (1H, d, J=8Hz), 7.10-7.57 (9H, m), 7.74 (1H, d, J=8Hz), 8.23(1H, d, J=8Hz), 8.87 (1H, s)

[1325] Mass: m/e=469 (M⁺+1)

EXAMPLE 6(2)

[1326] The following compound was prepared in a similar manner to thatof Example 3.

[1327]N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-1-(3-azabicyclo[3.2.2]non-3-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1328] mp: 95-100° C.

[1329] IR(KBr): 2932, 1653, 1558, 1456, 1204, 774 cm⁻¹

[1330]¹H-NMR (CDCl₃, δ): 0.78 (3H, d, J=8Hz), 0.88 (3H, d, J=8Hz),1.57-1.88 (8H, m), 2.08 (3H, br), 2.78 (3H, s), 2.50 (1H, dd, J=16Hz,J=16Hz), 2.88 (1H, dd, J=8Hz, J=16Hz), 3.48-3.85 (4H, m), 4.20 (1H, d,J=18Hz), 5.00 (1H, d, J=18Hz), 5.48 (1H, d, J=8Hz), 6.69-7.55 (10H, m)

[1331] Mass: m/e=530 (M⁺+1)

EXAMPLE 6(3)

[1332] The following compound was prepared in a similar manner to thatof Example 3.

[1333]N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-1-(2-methylcarbonylthiophen-3-yl)methyl-2-oxo-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1334] mp: 215-218° C.

[1335] IR(KBr): 3347, 2954, 1664, 1646, 1561, 1490, 1448, 1415, 1384,1310, 1216, 1165, 772 cm⁻¹

[1336]¹H-NMR (DMSO-d₆, δ): 0.70 (3H, d, J=8Hz), 0.80 (3H, d, J=8Hz),1.70-1.80 (1H, m), 2.18 (3H, s), 2.40 (3H, s), 2.50 (1H, dd, J=16Hz,J=16Hz), 2.78 (1H, dd, J=8Hz, J=16Hz), 5.10 (1H, d, J=18Hz), 5.16 (1H,d, J=8Hz), 5.40 (1H, d, J=16Hz), 6.68 (1H, d, J=8Hz), 6.85 (1H, d,J=8Hz), 7.03-7.13 (3H, m), 7.23-7.33 (3H, m), 7.49 (1H, t, J=8Hz), 7.71(1H, d, J=10Hz), 7.78 (1H, d, J=6Hz), 8.81 (1H, s)

[1337] Mass: m/e=502 (M⁺+1)

EXAMPLE 7

[1338] The following compound was prepared in a similar manner to thatof Example 4.

[1339]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-tetrazolyphenyl)urea

[1340] mp: 212-215° C.

[1341] IR(KBr): 3364, 2935, 1659, 1569, 1452, 1385, 1215, 1016, 761 cm⁻¹

[1342]¹H-NMR (DMSO-d₆, δ): 0.74 (3H, d, J=8Hz), 0.85 (3H, d, J=8Hz),1.03 (2H, d, J=6Hz), 1.20-1.82 (8H, m), 2.02 (2H, br), 2.43 (1H, dd,J=16Hz, J=16Hz), 2.95 (1H, dd, J=8Hz, J=16Hz), 3.47 (2H, d , J=18Hz),3.66 (1H, dd, J=8Hz, J=16Hz), 3.83 (1H, dd, J=8Hz, J=16Hz), 4.52 (1H, d,J=18Hz), 4.95 (1H, d, J=18Hz), 5.18 (1H, d, J=8Hz), 7.27-7.79 (8H, m),8.05 (1H, s), 9.22 (1H, s)

[1343] Mass: m/e=584 (M⁺+1)

EXAMPLE 8(1)

[1344] The following compound was prepared in a similar manner to thatof Example 6(1).

[1345]N-[(3RS)-2,3-dihydro-5-methyl-1-(3-methylpyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1346] mp: 225-229° C.

[1347] IR(KBr): 3323, 1677, 1644, 1611, 1562, 1492, 1449, 1387, 1312,1217, 1165, 776 cm⁻¹

[1348]¹H-NMR (DMSO-d₆, δ): 1.58 (3H, d, J=8Hz), 2.26 (3H, s), 4.27 (1H,d, J=16Hz), 4.60 (1H, d, J=16Hz), 5.33 (1H, q, J=8Hz), 6.76 (1H, s),6.78 (1H, d, J=8Hz), 6.99-7.26 (13H, m), 9.01 (1H, s)

[1349] Mass: m/e=427 (M⁺)

EXAMPLE 8(2)

[1350] The following compound was prepared in a similar manner to thatof Example 3.

[1351]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1352] mp: 150-153° C.

[1353] IR(KBr): 3343, 2931, 1959, 1675, 1554, 1206, 1167 cm⁻¹

[1354]¹H-NMR (DMSO-d₆, δ): 1.03 (2H, d, J=6Hz), 1.50-1.70 (8H,m), 1.98(1H, br), 2.04 (1H, br), 2.23 (3H, s), 2.40 (3H, s), 3.48 (1H, br),3.58-3.69 (2H, m), 4.65 (1H, d, J=16Hz), 4.90 (1H, d, J=16Hz), 5.10 (1H,d, J=8Hz), 6.72 (1H, J=8Hz), 7.07-7.18 (3H, m), 7.31-7.38 (2H, m), 7.60(1H, t, J=8Hz), 7.78 (1H, d, J=8Hz), 8.90 (1H, s)

[1355] Mass: m/e=487 (M⁺+1)

EXAMPLE 8(3)

[1356] The following compound was prepared in a similar manner to thatof Example 3.

[1357]N-[(3RS)-1-(2-acetylthiophen-3-yl)methyl-2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1358] mp: 215-219° C.

[1359] IR(KBr): 3307, 1676, 1554, 1491, 1449, 1415, 1382, 1311, 1217,1165, 770 cm⁻¹

[1360]¹H-NMR (DMSO-d₆, δ): 2.23 (3H, s), 2.44 (3H, s), 5.18 (1H, d,J=8Hz), 5.30 (1H, d, J=16Hz), 5.41 (1H, d, J=16Hz), 6.72-6.76 (2H, m),7.08-7.37 (9H, m), 7.56 (1H, t, J=8Hz), 7.79 (1H, d, J=8Hz), 7.83 (1H,d, J=6Hz), 8.91 (1H, s)

[1361] Mass: m/e=461 (M⁺+1)

EXAMPLE 9(1)

[1362] The following compound was prepared in a similar manner to thatof Example 6(1).

[1363]N-[(3RS)-2,3-dihydro-5-(3-methylbutyl)-1-(3-methylpyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1364] mp: 151-154° C.

[1365] IR(KBr): 2955, 1644, 1612, 1555, 1492, 1384, 1308, 1206, 1165,778, 692 cm⁻¹

[1366]¹H-NMR (DMSO-d₆, δ): 0.74 (3H, q, J=8Hz), 0.81 (3H, d,J=8Hz),1.17-1.50 (3H, m), 2.17 (3H, s), 2.45-2.76 (2H, m), 3.33 (3H, s),4.92 (1H, d, J=16Hz), 5.05 (1H, d, J=18Hz), 5.12 (1H, d, J=16Hz), 5.20(1H, d, J=18Hz), 6.67 (1H, d, J=8Hz), 7.02-7.27 (5H, m), 7.46-7.51 (2H,m), 7.66 (1H, d, J=8Hz), 7.71 (1H, d, J=8Hz), 8.11 (1H, d, J=6Hz), 8.83(1H, d, J=16Hz)

[1367] Mass: m/e=484 (M⁺+1)

EXAMPLE 9(2)

[1368] The following compound was prepared in a similar manner to thatof Example 6(3).

[1369]N-[(3RS)-1-(2-acetylthiophen-3-yl)methyl-2,3-dihydro-5-(3-methylbutyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1370] mp: 190-195° C.

[1371] IR(KBr): 3329, 2955, 1645, 1551, 1492, 1413, 1383, 1215, 1165,774 cm⁻¹

[1372]¹H-NMR (CDCl₃, δ): 0.80 (3H, t, J=8Hz), 0.85 (3H, d, J=8Hz),1.20-1.54 (3H, m), 1.68 (2H, s), 2.27 (3H, s), 2.49 (3H, s), 2.75 (2H,d, J=10Hz), 5.34 (1H, d, J=18Hz), 5.52 (1H, d, J=8Hz), 5.65 (1H, d,J=18Hz), 6.80-7.56 (10, m)

[1373] Mass: m/e=517 (M⁺+1)

EXAMPLE 10

[1374] The following compound was prepared in a similar manner to thatof Example 3.

[1375]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-ethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1376] mp: 115-120° C.

[1377] IR(KBr): 3358, 2963, 2932, 2866, 1659, 1630, 1569, 1489, 1451,1265, 1214, 1204, 1016 cm⁻¹

[1378]¹H-NMR (CDCl₃, δ): 1.14 (3H, t, J=7.2Hz), 1.50-1.80 (8H, m),2.00-2.10 (2H, m), 2.27 (3H, s), 2.73-2.95 (2H, m), 3.40-3.80 (4H, m),4.50 (1H, d, J=16.0Hz), 4.87 (1H, d, J=16.0Hz), 5.51 (1H, d, J=7.2Hz),6.66 (1H, s), 6.80-7.60 (9H, m)

EXAMPLE 1

[1379] The following compound was prepared in a similar manner to thatof Example 2.

[1380]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-butyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1381] mp: 121-123° C.

[1382] IR(KBr): 3348, 2931, 2864, 1659, 1599, 1555, 1490, 1451, 1202,774 cm⁻¹

[1383]¹H-NMR (CDCl₃, δ): 0.85 (3H, t, J=7.6Hz), 1.29 (2H, q, J=7.2Hz),1.40-1.80 (10H, m), 2.00-2.10 (2H, m), 2.27 (3H, s), 2.72-2.88 (2H, m),3.44-3.80 (4H, m), 4.39 (1H, d, J=16.4Hz), 4.91 (1H, d, J=16.4Hz), 5.49(1H, d, J=7.2Hz), 6.80-7.57 (10H, m)

[1384] Mass: m/e=530 (M⁺+1)

EXAMPLE 12(1)

[1385] The following compound was prepared in a similar manner to thatof Example 1(1).

[1386]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexylmethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea

[1387] mp: 164-166° C.

[1388] IR(KBr): 2916, 2846, 2400, 1678, 1657, 1592, 1556, 1476, 1444,1194 cm⁻¹

[1389]¹H-NMR (DMSO-d₆, δ): 0.80-1.20 (4H, m), 1.50-1.80 (15H, m),1.99-2.05 (2H, m), 2.23 (3H, s), 2.50-2.55 (1H, m), 2.95-2.98 (1H, m),3.43-3.79 (4H, m), 4.64 (1H, d, J=17Hz), 4.93 (1H, d, J=17Hz), 5.20 (1H,d, J=4.0Hz), 6.73 (1H, d, J=7.0Hz), 7.07-7.24 (3H, m), 7.35-7.42 (3H,m), 7.65 (1H, t, J=8Hz), 7.82 (1H, d, J=7.0Hz), 9.04 (1H, s)

[1390] Mass: m/e=571 (M⁺+1)

EXAMPLE 12(2)

[1391] The following compound was prepared in a similar manner to thatof Example 4.

[1392]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexylmethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea

[1393] mp: 218-222° C. (dec.)

[1394] IR(KBr): 3370, 3354, 2925, 2862, 1689, 1740, 1630, 1489, 1450,1214, 1204 cm⁻¹

[1395]¹H-NMR (DMSO-d₆, δ): 0.80-1.2 (4H, m), 1.50-1.80 (15H, m),1.90-2.40 (2H, m), 2.40-2.50 (1H, m), 2.80-2.90 (1H, m), 3.50-3.80 (4H,m), 4.56 (1H, d, J=17Hz), 4.95 (1H, d, J=17Hz), 5.14 (1H, d, J=8.0Hz),7.29 (1H, d, J=8.0Hz), 7.36-7.48 (4H, m), 7.56-7.63 (2H, m), 7.76 (1H,d, J=8.0Hz), 8.07 (1H, s), 9.20 (1H, s)

[1396] Mass: m/e=623 (M⁺)

EXAMPLE 13-1

[1397]N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-methoxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1398] mp: 193.9-195.2° C.

[1399] IR (Nujol, cm⁻¹): 1650

[1400]¹H-NMR (DMSO-d₆, δ): 2.5 (3H, br, s), 3.95 (3H, s), 4.66 (1H, d,J=18.0Hz), 5.40 (1H, d, J=3Hz), 5.46 (1H, d, J=18.0Hz), 6.9-7.8 (15H,m), 7.95 (1H, br, s), 8.21 (1H, br, s), 9.35 (1H, br, s)

[1401] Mass (APCI): 619 (M⁺+1)

EXAMPLE 13-2

[1402] A mixture ofN-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-methoxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(200 mg) and 1N boron tribromide in methylene chloride (3.87 ml) wasstirred at 0° C. under nitrogen stream for 4 hours and allowed to standin a refrigerator overnight. Ethyl acetate and water were added to thereaction mixture. The separated organic layer was washed with water andbrine, and then dried over magnesium sulfate. The solvent was evaporatedin vacuo to afford a pale brown powder, which was washed withdiisopropyl ether and collected by filtration to giveN-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(202.0 mg) as a crystalline powder.

[1403] mp: 220.8-225.0° C.

[1404] IR (Nujol, cm⁻¹): 1640

[1405]¹H-NMR (DMSO-d₆, δ): 4.67 (1H, d, J=18.1Hz), 5.56 (1H, d,J=18.1Hz), 6.7-7.9 (15H, m), 8.22 (1H, br, s), 9.37 (1H, br, s)

[1406] Mass (FAB): 605 (M⁺+1)

EXAMPLE 13-3

[1407] A mixture ofN-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(150 mg), triethylamine (75 mg) and chlorotriphenylmethane (69 mg) in amixture of N,N-dimethylformamide and tetrahydrofuran (1:3, 4 ml) wasstirred overnight. Ethyl acetate and a saturated aqueous solution ofsodium bicarbonate were added to the reaction mixture. The separatedorganic layer was washed with water and brine, and then dried oversodium sulfate. The solvent was evaporated in vacuo to afford anamorphous mass, which was triturated in diisopropyl ether and collectedby filtration to affordN-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-{3-[1-(triphenylmethyl)tetrazol-5-yl]phenyl}urea(186.0mg, 88.6% yield) as a crystalline powder.

[1408] mp: 132.1-146.0° C.

[1409] IR (Nujol, cm⁻¹): 1640

[1410]¹H-NMR (DMSO-d₆, δ): 2.5 (3H, br, s), 4.81 (1H, d, J=18.4Hz), 5.39(1H, d, J=8.4Hz), 5.68 (1H, d, J=18.0Hz), 6.8-7.8 (30H, m), 8.08 (1H,br, s)

[1411] Mass (FAB): 847 (M⁺+1)

EXAMPLE 13-4

[1412]N-[(3RS)-1-(2-Ethoxycarbonylmethoxyphenyl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-{3-[1-(triphenylmethyl)tetrazol-5-yl]phenyl}ureawas prepared in a similar manner to that of Preparation 59-3.

[1413] IR (Neat, cm⁻¹): 1700

[1414]¹H-NMR (DMSO-d₆, δ): 0.97 (3H, t, J=7.1Hz), 2.30 (3H, s), 3.89(2H, q, J=7.1Hz), 4.21 (1H, d, J=16.8Hz), 4.68 (1H, d, J=16.8Hz), 5.05(2H, s), 5.20 (1H, d, J=8.6Hz), 7.0-7.8 (30H, m), 8.50 (1H, d, J=8.5Hz)

EXAMPLE 13-5

[1415] A mixture ofN-[(3RS)-1-(2-ethoxycabonylmethoxyphenyl)-carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-{3-[1-(triphenylmethyl)tetrazol-5-yl]phenyl}urea(196 mg) and 1N NaOH in 1,2-dimethoxyethane (2 ml) was stirred at roomtemperature overnight. 4N-HCl in ethyl acetate (2 ml) was added to thereaction mixture and stirred at room temperature for three days. Ethylacetate and water were added to the reaction mixture. The separatedorganic layer was washed with water and brine successively, and driedover magnesium sulfate. Removal of the solvent in vacuo affordedN-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-carboxymethoxyphenyl)-carbonylmethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(66.0 mg, 47.4%).

[1416] mp: 109.6-113.0° C.

[1417]¹H-NMR (DMSO-d₆, δ): 4.04 (1H, d, J=17.0Hz), 4.64 (1H, d,J=17.0Hz), 5.05 (2H, s), 5.18 (1H, d, J=8.6Hz), 7.03 (1H, d, J=7.6Hz),7.2-7.7 (13H, m), 8.46 (1H, d, J=8.6Hz)

[1418] Mass (FAB): 662 (M⁺)

EXAMPLE 14-1

[1419] A mixture ofN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-hydroxymethylphenyl)urea(190 mg) and activated manganese dioxide (1.5 g) in acetone (10 ml) wasstirred at room temperature for 4 hours.

[1420] The reaction mixture was filtered. The filtrate and the washingswere combined and evaporated in vacuo to afford a colorless oil, whichwas triturated in diisopropyl ether and collected by filtration toaffordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-formylphenyl)urea(146 mg, 77.1%) as a crystalline powder.

[1421] mp: 236.8-242.1° C.

[1422] IR (Nujol, cm⁻¹): 1700, 1680, 1635

[1423]¹H-NMR (DMSO-d₆, δ): 1.4-2.2 (10H, m), 2.44 (3H, s), 2.9-3.4 (2H,m), 3.7-4.0 (2H, m), 4.13 (1H, d, J=16.1Hz), 5.13 (1H, d, J=16.1Hz),5.32 (1H, d, J=8.3Hz), 7.03 (1H, d, J=7.6Hz), 7.1-7.4 (3H, m), 7.4-7.8(6H, m), 8.0 (1H, br, s), 9.32 (1H, br, s), 9.94 (1H, br, s)

[1424] Mass (APCI): 596 (M⁺+1)

EXAMPLE 14-2

[1425]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-hydroxyiminomethylphenyl)ureawas prepared in a similar manner to that of Example 16(7)-2.

[1426] mp: 196.0-199.0° C.

[1427] IR (Nujol, cm⁻¹): 3300, 1680, 1640

[1428]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.9-3.4 (2H,m), 3.6-4.0 (2H, m), 4.12 (1H, d, J=16.2Hz), 5.13 (1H, d, J=16.2Hz),5.31 (1H, d, J=8.4Hz), 7.0-7.8 (12H, m), 8.05 (1H, s), 11.18 (1H, s)

[1429] Mass (APCI): 611 (M⁺+1)

EXAMPLE 15-1

[1430]N-[(3RS)-1-(2-aminophenacyl)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1431] mp: 164.1-186.2° C.(dec.)

[1432] IR (Nujol, cm⁻¹): 1650

[1433]¹H-NMR (DMSO-d₆, δ): 2.5 (3H, br, s), 4.69 (1H, d, J=17.4Hz), 5.41(1H, d, J=8.3Hz), 5.69 (1H, d, J=17.4Hz), 6.5-8.2 (16H, m), 9.37 (1H,br, s)

[1434] Mass (APCI): 604 (M⁺+1)

EXAMPLE 15-2

[1435] A mixture ofN-[(3RS)-1-(2-aminophenacyl)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(180 mg) and acetic anhydride (2 ml) in methylene chloride (2 ml) wasstirred at room temperature for 6 hours. The reaction mixture wasevaporated in vacuo to afford a residue, which was triturated indiisopropyl ether and collected by filtration to giveN-[(3RS)-1-(2-(N,N-diacetylamino)phenacyl)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(125.0 mg, 61.0% yield) as a crystalline powder.

[1436] mp: 192.0-216.6° C. (dec.)

[1437] IR (Nujol, cm⁻¹): 1670, 1645

[1438]¹H-NMR (DMSO-d₆, δ): 1.91 (6H, s), 2.49 (3H, s), 4.75 (1H, d,J=17.8Hz), 5.44 (1H, d, J=8.3Hz), 5.85 (1H, d, J=17.8Hz), 7.0-7.8 (13H,m), 8.0-8.4 (3H, m), 9.37(1H, br, s)

[1439] Mass (FAB): 688 (M⁺+1)

EXAMPLE 16(1)

[1440]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-3-yl]-N′-(3-bromophenyl)ureawas prepared in a similar manner to that of Example 59.

[1441] mp: >250° C.

[1442] IR (Nujol, cm⁻¹): 1690, 1630

[1443]¹H-NMR (DMSO-d6, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.8-3.4 (2H,m), 3.4-4.0 (2H, m), 4.13 (1H, d, J=16.2Hz), 5.13 (1H, d, J=16.2Hz),5.30 (1H, d, J=8.4Hz), 7.0-7.9 (11H, m), 9.22 (1H, br, s)

[1444] Mass (APCI): 648, 646

EXAMPLE 16(2)

[1445]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-chlorophenyl)ureawas prepared in a similar manner to that of Example 59.

[1446] mp: >250° C.

[1447] IR (Nujol, cm⁻¹): 1680, 1630

[1448]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.9-3.4 (2H,m), 3.5-4.0 (2H, m), 4.13 (1H, d, J=16.2Hz), 5.13 (1H, d, J=16.2Hz),5.31 (1H, d, J=8.3Hz ), 6.9-7.8 (11H, m), 9.24 (1H, s)

[1449] Mass (APCI): 602 (M⁺+1)

EXAMPLE 16(3)

[1450]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-(2-fluorophenyl)-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methoxyphenyl)ureawas prepared in a similar manner to that of Example 59.

[1451] mp: 240.9-243.1° C.

[1452] IR (Nujol, cm⁻¹): 1680, 1640

[1453]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.8-3.1 (1H,m), 3.1-3.3 (1H, m), 3.5-4.0 (2H, m), 3.69 (3H, s), 4.12 (1H, d,J=16.2Hz), 5.13 (1H, d, J=16.1Hz), 5.32 (1H, d, J=8.5Hz), 6.50 (1H, d,J=7.8Hz), 6.7-7.0 (1H, m), 7.0-7.8 (10H, m), 9.04 (1H, br, s)

[1454] Mass (APCI): 598 (M⁺+1)

EXAMPLE 16(4)

[1455]N-[(3RS)-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)methylphenyl]ureawas prepared in a similar manner to that of Example 51.

[1456] mp: 153.8-167.7° C.

[1457] IR (Nujol, cm⁻¹): 1650

[1458]¹H-NMR (DMSO-d₆, δ): 1.4-2.1 (10H, m), 2.44 (3H, s), 2.9-4.0 (4H,m), 4.12 (1H, d, J=16.2Hz), 4.22 (2H, br, s), 2.12 (1H, d, J=16.2Hz),5.30 (1H, d, J=8.4Hz), 6.8-7.8 (12H, m), 8.0-8.2 (1H, m), 9.05 (1H, br,s)

[1459] Mass (APCI): 650 (M⁺+1)

EXAMPLE 16(5)

[1460]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylthiophenyl)ureawas prepared in a similar manner to that of Example 59.

[1461] mp: 234.2-236.6° C.

[1462] IR (Nujol, cm⁻¹): 1700, 1675, 1630

[1463]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.42 (3H, s), 2.44 (3H, s),2.9-3.4 (2H, m), 3.7-4.0 (2H, m), 4.12 (1H, d, J=16.2Hz), 5.13 (1H, d,J=16.2Hz), 5.32 (1H, d, J=8.4Hz), 6.7-6.9 (1H, m), 6.9-7.1 (2H, m),7.1-7.4 (4H, m), 7.4-7.8 (4H, m), 9.08 (1H, br, s)

[1464] Mass (APCI): 614 (M⁺+1)

EXAMPLE 16(6)

[1465]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1466] mp: 246.2-247.2° C.

[1467] IR (Nujol, cm⁻¹): 1700, 1680, 1635

[1468]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.23 (3H, s), 2.44 (3H, s),2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.12 (1H, d, J=16.2Hz), 5.12 (1H, d,J=16.2Hz), 5.32 (1H, d, J=8.5Hz), 6.73(1H, d, J=6.6Hz), 7.0-7.8 (11H,m), 8.94 (1H, br, s)

[1469] Mass (APCI): 582 (M⁺+1)

EXAMPLE 16(7)-1

[1470]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-acetylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1471] mp: >250° C.

[1472] IR (Nujol, cm⁻¹): 1700, 1680, 1640

[1473]¹H-NMR (DMSO-d₆, δ): 1.4-2.2 (10H, m), 2.44 (3H, s), 2.53 (3H, s),2.9-3.3 (2H, m), 3.7-4.1 (2H, m), 4.13 (1H, d, J=16.2Hz), 5.13 (1H, d,J=16.2Hz), 5.33 (1H, d, J=8.4Hz), 7.03 (1H, d, J=7.6Hz) 7.2-7.9 (10H,m), 8.01 (1H, br, s), 9.26 (1H, br, s)

[1474] Mass (APCI): 610 (M⁺+1)

EXAMPLE 16(7)-2

[1475] A mixture ofN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-acetylphenyl)urea(217 mg) and hydroxylamine-hydrochloride (124 mg), triethylamine (180mg) in tetrahydrofuran (4 ml) was stirred at room temperature overnight.Ethyl acetate and 1N aqueous hydrochloric acid solution were added tothe reaction mixture. The separated organic layer was washed with 1Naqueous hydrochloric acid twice, saturated aqueous sodium bicarbonate,and brine successively and then dried over magnesium sulfate. Thesolvent was evaporated in vacuo to affordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(1-hydroxyiminoethyl)phenyl]urea(235.0 mg) as a crystalline powder.

[1476] mp: 199.1-207.8° C.

[1477] IR (Nujol, cm⁻¹): 1650

[1478]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.11 (3H, s), 2.44 (3H, s),2.8-3.4 (2H, m), 3.6-4.0 (2H, m), 4.13 (1H, d, J=16.3Hz), 5.13 (1H, d,J=16.3Hz), 5.33 (1H, d, J=8.4Hz), 7.02 (1H, d, J=7.6Hz), 7.2-7.8 (11H,m), 9.10 (1H, br, s), 11.14 (1H, br, s)

[1479] Mass (APCI): 625 (M⁺+1)

EXAMPLE 16(8)

[1480]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1481] mp: 182.2-190.9° C.

[1482]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.45 (3H, s), 2.9-3.4 (2H,m), 3.6-4.0 (2H, m), 4.13 (1H, d, J=16.3Hz), 5.14 (1H, d, J=16.3Hz),5.35 (1H, d, J=8.3Hz), 6.9-7.1 (2H, m), 7.2-7.4 (3H, m), 7.4-7.8 (5H,m), 8.0-8.2 (1H, m), 8.20 (1H, br, s), 9.30 (1H, br, s)

[1483] Mass (APCI): 636 (M⁺+1)

EXAMPLE 16(9)-1

[1484]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-tert-butoxycarbonylphenyl)ureawas prepared in a similar manner to that of Example 51.

[1485] mp: 230.4-232.2° C.

[1486] IR (Nujol, cm³¹ ¹): 1720, 1680

[1487]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 1.52 (9H, s),2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.13 (1H, d, J=16.2Hz), 5.13 (1H, d,J=16.2Hz), 5.32 (1H, d, J=8.4Hz), 7.03 (1H, d, J=7.5Hz), 7.2-7.8 (11H,m), 7.95 (1H, br, s), 9.52 (1H, br, s)

[1488] Mass (APCI): 668 (M⁺+1)

EXAMPLE 16(9)-2

[1489]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-carboxyphenyl)ureawas prepared in a similar manner to that of Example 18(3)-2.

[1490] mp: 197.1-204.2° C.

[1491]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.45 (3H, s), 2.9-3.4 (2H,m), 3.8-4.0 (2H, m), 4.13 (1H, d, J=16.2Hz), 5.13 (1H, d, J=16.2Hz),5.32 (1H, d, J=8.3Hz), 7.0-7.1 (1H, m), 7.2-7.8 (10H, m), 8.05 (1H, br,s), 9.24 (1H, br, s)

EXAMPLE 17(1)

[1492]N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1493] mp: 198.9-200.7° C.

[1494] IR (Nujol, cm⁻¹): 1655

[1495]¹H-NMR (DMSO-d₆, δ): 0.8-2.0 (10H, m), 2.3-2.5 (3H, br, s),2.9-3.1 (1H, m), 3.09 (3H, s), 5.12 (1H, d, J=8.4Hz), 7.3-7.7 (7H, m),8.18 (1H, br, s), 9.31(1H, br, s)

[1496] Mass (APCI): 473 (M⁺+1)

EXAMPLE 17(2)

[1497]N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1498] mp: 196.4-197.5° C.

[1499] IR (Nujol, cm⁻¹): 1685, 1640, 1610

[1500]¹H-NMR (DMSO-d₆, δ): 0.8-2.0 (10H, m), 2.22 (3H, s), 2.34 (3H, s),3.04 (1H, m), 3.07 (3H, s), 5.08 (1H, d, J=8.3Hz), 6.73 (1H, m), 7.0-7.6(7H, m), 8.91 (1H, br, s)

[1501] Mass (APCI): 419 (M⁺+1)

EXAMPLE 18(1)

[1502]N-[(3RS)-1-(2-Methylphenacyl)-9-methyl-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1503] mp: 190.2-196.2° C.

[1504] IR (Nujol, cm⁻¹): 1680, 1635

[1505]¹H-NMR (DMSO-d₆, δ): 2.24 (3H, s), 2.27 (3H, s), 2.46 (3H, s),4.70 (1H, d, J=17.5Hz), 5.37 (1H, d, J=8.6Hz), 5.45 (1H, d, J=17.5Hz),6.73 (1H, d, J=6.6Hz), 7.0-8.0 (15H, m), 8.96 (1H, br, s)

[1506] Mass (APCI): 549 (M⁺+1)

EXAMPLE 18(2)

[1507]N-[(3RS)-1-(2-Methylphenacyl)-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea was prepared in a similar manner tothat of Example 51.

[1508] mp: 215.8-220.3° C.

[1509] IR (Nujol, cm⁻¹): 1670, 1635

[1510]¹H-NMR (DMSO-d, δ): 2.28 (3H, s), 2.49 (3H, s), 4.72 (1H, d,J=17.5Hz), 5.41 (1H, d, J=8.3Hz), 5.47 (1H, d, J=17.5Hz), 7.0-8.0 (15H,m), 8.21 (1H, br, s), 9.33 (1H, br, s)

[1511] Mass (APCI): 603 (M⁺+1)

EXAMPLE 18(3)-1

[1512]N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methyl-phenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tert-butoxycarbonyl)-phenyl]ureawas prepared in a similar manner to that of Example 51.

[1513] IR (Nujol, cm⁻¹): 1710, 1660

[1514]¹H-NMR (CDCl₃, δ): 1.56 (9H, s), 2.31 (3H, s), 2.45 (3H, s), 4.38(1H, d, J=17.2Hz), 5.58 (1H, d, J=17.2Hz), 5.73 (1H, d, J=8.3Hz),6.8-8.1 (15H, m)

[1515] Mass (APCI): 635 (M⁺+1)

EXAMPLE 18(3)-2

[1516] A mixture ofN-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-tert-butoxycarbonylphenyl)urea(170 mg) and trifluoroacetic acid (1.0 ml) in methylene chloride (2.0ml) was stirred at 0° C. for 2 hours. The reaction mixture wasevaporated in vacuo to give a residue, which was washed with diisopropylether to affordN-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-carboxyphenyl)urea(152.0 mg,98.0%) as a crystalline powder.

[1517] mp: 168.1-176.3° C.

[1518] IR (Nujol, cm⁻¹): 1650

[1519]¹H-NMR (DMSO-d₆, δ): 2.27 (3H, s), 2.48 (3H, s), 4.70 (1H, d,J=17.5Hz), 5.38 (1H, d, J=8.4Hz), 5.46 (1H, d, J=17.5Hz), 7.0-7.8 (14H,m), 7.8-7.9 (1H, m), 8.05 (1H, br, s), 9.24 (1H, br, s)

[1520] Mass (FAB): 579 (M⁺+1)

EXAMPLE 19(1)

[1521]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-ethyl-5-(2-fluorophenyl)-2-oxo-1H-1.4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1522] mp: 162.8-168.1° C.

[1523] IR (Nujol, cm⁻¹): 1680, 1640

[1524]¹H-NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.4Hz), 1.3-2.2 (10H, br),2.78 (2H, q, J=7.4Hz), 2.9-3.5 (2H, m), 3.7-4.0 (2H, m), 4.03 (1H, d,J=16.2Hz), 5.19 (1H, d, J=16.2Hz), 5.31 (1H, d, J=8.5Hz), 6.73(1H, d,J=6.7Hz), 6.9-7.8 (11H, m), 8.94 (1H, br, s)

[1525] Mass (APCI): 596 (M⁺+1)

EXAMPLE 19(2)

[1526]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethy]-2,3-dihydro-9-ethyl-5-(2-fluorophenyl)-2-oxo-1H-1.4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1527] mp: 226.4-231.6° C.

[1528] Mass(APCI): 650 (M⁺+1)

[1529] IR (Nujol, cm⁻¹): 1680, 1630

[1530]¹H-NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.4Hz), 1.3-2.2 (10H, br),2.79 (2H, q, J=7.4Hz), 2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.04 (1H, d,J=16.4Hz), 5.21 (1H, d, J=16.4Hz), 5.34 (1H, d, J=8.3Hz), 7.03(1H, d,J=7.6Hz), 7.2-7.8 (11H, m), 8.20 (1H, br, s), 9.31 (1H, br, s)

EXAMPLE 20(1)

[1531]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl)ureawas prepared in a similar manner to that of Example 51.

[1532] mp: 212.2-222.1° C.

[1533] IR (Nujol, cm⁻¹): 1650

[1534]¹H-NMR (DMSO-d₆, δ): 1.12 (3H, d, J=6.5Hz), 1.41 (3H, d, J=6.6Hz),1.3-2.2 (10H, m), 2.9-4.0 (6H, m), 5.32 (1H, d, J=17.9Hz), 5.34 (1H, d,J=8.2Hz), 6.9-7.1 (1H, m), 7.1-7.8 (11H, m), 8.19 (1H, br, s), 9.31 (1H,br, s)

[1535] Mass (APCI): 664 (M⁺+1)

EXAMPLE 20(2)

[1536]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1537] mp: 183.3-186.8° C.

[1538] IR (Nujol, cm⁻¹): 1655

[1539]¹H-NMR (DMSO-d₆, δ): 1.11 (3H, d, J=6.5Hz), 1.40 (3H, d, J=6.7Hz),1.4-2.2 (10H, m), 2.8-3.4 (3H, m), 3.6-4.0 (3H, m), 5.30 (1H, d,J=14.9Hz), 5.31 (1H, d, J=8.6Hz), 6.74 (1H, d, J=6.5Hz), 6.9-7.8 (11H,m), 8.92 (1H, br, s)

[1540] Mass (APCI): 610 (M⁺+1)

EXAMPLE 21-1

[1541]N-[(3RS)-1-(2-Acetoxyethyl)-5-cyclohexyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1542] mp: 165.2-168.4° C.

[1543] IR (Nujol, cm⁻¹): 1745, 1660

[1544]¹H-NMR (DMSO-d₆, δ): 1.0-2.0 (10H, m), 1.79 (3H, s), 2.34 (3H, s),3.00 (1H, m), 3.3-3.6 (1H, m), 3.7-3.9 (2H, m), 4.4-4.6 (1H, m), 5.06(1H, d, J=8.3Hz), 7.3-7.7 (7H, m), 8.16 (1H, br, s), 9.27 (1H, br, s)

[1545] Mass (APCI): 545 (M⁺+1)

EXAMPLE 21-2

[1546]N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1-(2-hydroxyethyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Preparation 59-4.

[1547] mp: 223.5-224.2° C.

[1548] IR (Nujol, cm⁻¹): 1640

[1549]¹H-NMR (DMSO-d₆, δ): 0.9-2.0 (10H, m), 2.34 (3H, s), 2.9-3.6 (4H,m), 4.2-4.4 (1H, m), 5.02 (1H, d, J=8.2Hz), 7.3-7.7 (7H, m), 8.17 (1H,s), 9.29 (1H, br, s)

[1550] Mass (APCI): 503 (M⁺+1)

EXAMPLE 22(1)

[1551] Potassium salt ofN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(1-sulfoethyl)phenyl]ureawas prepared in a similar manner to that of Example 22(3).

[1552] mp: 247.2-255.6° C.

[1553] IR (Nujol, cm⁻¹): 1650, 1615

[1554]¹H-NMR (DMSO-d₆, δ): 1.2-2.2 (1H, m), 1.43 (3H, d, J=7.1Hz), 2.44(3H, s), 2.9-3.4 (2H, m), 3.58 (1H, d, J=6.6Hz), 3.6-4.0 (2H, br, m),4.11 (1H, d, J=16.2Hz), 5.14 (1H, d, J=16.2Hz), 5.32 (1H, d, J=8.6Hz),6.8-7.0 (1H, br), 7.0-7.2 (2H, m), 7.2-7.8 (10H, m), 8.99 (1H, m)

[1555] Mass (FAB): 714 (M⁺+1)

EXAMPLE 22(2)

[1556]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-hydroxymethylphenyl)ureawas prepared in a similar manner to that of Example 22(3).

[1557] mp: 188.2-202.2° C.

[1558] IR (Nujol, cm⁻¹): 3320, 1640

[1559]¹H-NMR (DMSO-d₆, δ): 1.2-2.0 (10H, m), 2.26 (3H, s), 2.7-3.2 (2H,m), 3.7-3.9 (2H, m), 4.04 (1H, d, J=17.8Hz), 4.25 (1H, d, J=5.7Hz),4.8-5.1 (3H, m), 5.14 (1H, d, J=8.5Hz), 6.6-6.8 (1H, m), 6.8-6.9 (1H,m), 6.9-7.6 (10H, m), 8.82 (1H, br, s)

[1560] Mass (APCI): 598 (M⁺+1)

EXAMPLE 22(3)

[1561] A mixture of(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-3-(imidazol-1-yl)carbonylamino-9-methyl-1H-1,4-benzodiazepin-2-one(250 mg), 3-aminophenol (55 mg) and triethylamine (93 mg) inN,N-dimethylformamide (1 ml) was stirred at 100° C. for 1 hour. Afterthe reaction mixture was allowed to cool to room temperature, ethylacetate and 1N aqueous hydrochloric acid were added thereto. Theseparated organic layer was washed with 1N aqueous hydrochloric acid,water, saturated aqueous sodium bicarbonate and brine successively, andthen dried over magnesium sulfate. The solvent was evaporated in vacuoto give a colorless paste, which was washed with diisopropyl ether andcollected by filtration to affordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-hydroxyphenyl)urea(184.0 mg, 68.5% yield) as a crystalline.

[1562] mp: 192.8-203.9° C.

[1563] IR (Nujol, cm⁻¹): 3300, 1650

[1564]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.8-3.4 (2H,m), 3.7-4.0 (2H, m), 4.12 (1H, d, 16.2Hz), 5.13 (1H, d, J=16.2Hz), 5.30(1H, d, J=8.5Hz), 6.2-6.4 (1H, m), 6.7-7.7 (10H, m), 9.24 (1H, m)

[1565] Mass (APCI): 584 (M⁺+1)

EXAMPLE 23(1)

[1566](3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethy]-5-cyclohexyl-2,3-dihydro-3-(indol-2-yl)carbonylamino-9-methyl-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[1567] mp: 206.2-212.2° C.

[1568] IR (Nujol, cm⁻¹): 1680, 1640

[1569]¹H-NMR (DMSO-d₆, δ):1.0-2.2 (10H, m), 2.40 (3H, s), 2.8-3.4 (2H,m), 2.5-4.0 (2H, m), 4.02 (1H, d, J=16.0Hz), 5.02 (1H, d, J=16.1Hz),5.46 (1H, d, 8.1Hz), 7.0-7.8 (8H, m), 9.20 (1H, d, J=8.1Hz)

[1570] Mass (FAB): 580 (M⁺+1)

EXAMPLE 23(2)

[1571]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1572] mp: 186.2-197.6° C.

[1573] IR (Nujol, cm⁻¹): 1650

[1574]¹H-NMR (DMSO-d₆, δ): 0.9-2.2 (20H, m), 2.38 (4H, m), 2.8-4.0 (4H,m), 4.04 (1H, d, J=16.0Hz), 4.98 (1H, d, J=16.0Hz), 5.02 (1H, d,J=8.2Hz), 6.94 (1H, d, J=9.1Hz), 7.3-7.8 (5H, m), 8.1-8.3 (2H, m), 9.25(1H, br, s)

[1575] Mass (FAB): 624 (M⁺+1)

EXAMPLE 23(3)

[1576]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1577] mp: 212-214° C.

[1578] IR (Nujol, cm⁻¹): 3390, 3275, 1705, 1688, 1634

[1579]¹H-NMR (DMSO-d₆, δ): 1.05-2.1 (20H, m), 2.22 (3H, s), 2.37 (3H,s), 2.90 (1H, m), 3.05-3.35 (2H, m), 3.65-3.87 (2H, m), 4.49 (2H, d, d,J=16.2Hz, J=187Hz), 5.08 (1H, d, J=8.4Hz), 6.69-7.57 (8H, m), 8.85 (1H,s)

[1580] APCI-MS(e/z): 570 (M⁺+1)

EXAMPLE 24(1)

[1581]N-[(3RS)-5-Cyclohexyl-9-methyl-2,3-dihydro-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1582] mp: 165.0-176.6° C.

[1583] IR (Nujol, cm⁻¹): 1660, 1635

[1584]¹H-NMR (DMSO-d₆, δ): 1.0-2.2 (10H, m), 2.32 (3H, s), 2.41 (3H, s),2.9-3.2 (1H, m), 4.58 (1H, d, J=17.3Hz), 5.18 (1H, d, J=8.4Hz), 5.33(1H, d, J=17.3Hz), 6.9-7.0 (1H, m), 7.2-7.7 (9H, m), 7.7-7.9 (1H, m),8.0-8.2 (2H, m), 9.22 (1H, br, s)

[1585] Mass (FAB): 591 (M⁺+1)

EXAMPLE 24(2)

[1586](3RS)-5-Cyclohexyl-2,3-dihydro-3-(indol-2-yl)carbonylamino-9-methyl-1-(2-methylphenacyl)-1H-1,4-benzodiazepin-2-onewas prepared in a similar manner to that of Preparation 59-5.

[1587] mp: 126.7-145.2° C.

[1588] IR (Nujol, cm⁻¹): 1640

[1589]¹H-NMR (DMSO-d₆, δ): 1.0-2.3 (10H, m), 2.32 (3H, s), 2.43 (3H, s),3.05 (1H, m), 4.58 (1H, d, J=17.4Hz), 5.37 (1H, d, J=17.3Hz), 5.52 (1H,d, J=8.1Hz), 7.0-8.1 (12H, m), 9.2-9.3 (1H, m)

[1590] Mass (APCI): 547 (M⁺+1)

EXAMPLE 25-1

[1591] A mixture ofN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(208 mg) and 15% aqueous solution of sodium thiomethoxide inN,N-dimethylformamide was stirred at room temperature for 8 hours. Ethylacetate and water were added to the reaction mixture. The separatedorganic layer was washed with water and brine, and then dried overmagnesium sulfate. The solvent was evaporated in vacuo to afford a paste(214 mg), which was washed with diisopropyl ether and collected byfiltration to giveN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-hydroxymethyl-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methyphenyl)urea(127 mg, 66.0%yield) as a crystalline powder.

[1592] mp: 151.7-153.2° C.

[1593] IR (Nujol, cm⁻¹): 1640

[1594]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.22 (3H, s), 2.48 (3H, s),2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.01 (1H, d, J=16.3Hz), 4.5-4.6 (2H,m), 5.11 (1H, d, J=16.3Hz), 5.23 (1H, d, J=8.5Hz), 6.72 (1H, d,J=6.5Hz), 7.0-7.2 (3H, m), 7.2-7.7 (4H, m), 8.90 (1H, br, s)

[1595] Mass (APCI): 518 (M⁺+1)

EXAMPLE 25-2

[1596] To a mixture ofN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-hydroxymethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(147 mg) and diisopropylethylamine (55.1 mg) in methylene chloride (2ml) was added dropwise a solution of methanesulfonyl chloride (48.7 mg)in methylene chloride (1 ml) under stirring and cooling at 0-5° C. in anice-bath. The mixture was stirred for 1.5 hours under the sameconditions. The reaction mixture was evaporated in vacuo to afford aresidue, which was dissolved in tetrahydrofuran (2 ml) and cooled in anice-bath. To the solution prepared above was added 15% aqueous solutionof sodium methylmercaptide (0.5 g). The mixture was stirred undercooling for 0.5 hour and at ambient temperature for 2 hours. Thereaction mixture was evaporated in vacuo to afford a residue, which wasdissolved in ethyl acetate and washed with water twice. The separatedorganic layer was dried over magnesium sulfate and evaporated in vacuoto afford an amorphous mass, which was subjected to preparativethin-layer chromatography on silica gel developing with a mixture ofchloroform and methanol (10:1) to giveN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-methylthiomethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methyphenyl)ureaas an amorphous mass. This was triturated in diisopropyl ether andcollected by filtration to give a crystalline powder (71.9 mg, 41.7%yield).

[1597] mp: 172-175.5° C.(dec.)

[1598]¹H-NMR (CDCl₃, δ): 1.45-2.1 (10H, m), 2.20 (3H, s), 2.29 (3H, s),2.38 (3H, s), 3.25-3.55 (4H, m), 3.7-3.95 (3H, m), 5.03 (1H, d,J=15.8Hz), 5.54 (1H, d, J=8.2Hz), 6.7-7.8 (9H, m)

[1599] APCI-MS(m/z): 548 (M⁺+1)

EXAMPLE 26

[1600]N-[(S)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1601] mp: 210.3-213.4° C.

[1602] [α]_(D) ^(30.4)=+6.6° (C=0.50, EtOH)

[1603] IR (Nujol, cm⁻¹): 1650

[1604]¹H-NMR (DMSO-d₆, δ): 1.4-2.2 (10H, m), 2.45 (3H, s), 2.9-3.4 (2H,m), 3.4-4.0 (2H, m), 4.14 (1H , d, J=16.2Hz), 5.14 (1H, d, J=10.2Hz),5.35 (1H, d, J=8.3Hz), 6.8-7.8 (12H, m), 8.21 (1H, br, s), 9.31 (1H, br,s)

[1605] Mass (APCI): 636 (M⁺+1)

EXAMPLE 27

[1606]N-[(R)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1607] mp: 209.9-215.2° C.

[1608] [α]_(D) ^(30.4)=−10.96° (C=0.52, EtOH)

[1609] IR (Nujol, cm⁻¹): 1650, 1620

[1610]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.45 (3H, s), 2.8-4.0 (4H,m), 4.14 (1H, d, 16.3Hz), 5.14 (1H, d, 16.3Hz), 5.35 (1H, d, 8.3Hz),7.03 (1H, d, 7.5Hz), 7.2-7.8 (11H, m), 8.21 (1H, br, s), 9.32 (1H, br,s)

[1611] Mass (APCI): 636 (M⁺+1)

EXAMPLE 28

[1612]N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(pyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1613] mp: 173.9-182.0° C.

[1614] IR (Nujol, cm⁻¹): 1640

[1615]¹H-NMR (DMSO-d₆, δ): 4.59 (1H, d, J=15.3Hz), 5.35 (1H, d,J=8.3Hz), 5.49 (1H, d, J=15.3Hz), 6.9-7.8 (13H, m), 7.95 (1H, br, s),8.0-8.3 (2H, m), 9.33 (1H, br, s)

[1616] Mass (FAB): 562 (M⁺+1)

EXAMPLE 29

[1617]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-9-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1618] mp: 172.0-180.5° C.

[1619] IR (Nujol, cm⁻¹): 1650

[1620] hu 1H-NMR (DMSO-d₆, δ): 1.4-2.2 (10H, m), 2.9-3.1 (1H, m),3.1-3.5 (1H, m), 3.6-4.0 (2H, m), 4.41 (1H, d, J=16.4Hz), 5.22 (1H, d,J=16.8Hz), 5.38 (1H, d, J=8.3Hz), 6.93 (1H, d, J=9.2Hz), 7.2-8.3 (11H,m), 9.30 (1H, br, s)

[1621] Mass (APCI): 657 (M⁺+1)

EXAMPLE 30

[1622]N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-tert-butylcarbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)pheny]ureawas prepared in a similar manner to that of Example 51.

[1623] mp: 160.4-180.7° C.(dec.)

[1624] IR (Nujol, cm⁻¹): 1720, 1650

[1625] hu 1H-NMR (DMSO-d₆, δ): 1.09 (9H, s), 2.43 (3H, s), 4.19 (1H, d,J=17.3Hz), 5.24 (1H, d, J=17.4Hz), 5.32 (1H, d, J=8.4Hz), 7.07 (1H, d,J=7.2Hz), 7.2-7.8 (11H, m), 8.19 (1H, br, s), 9.27 (1H, br, s)

[1626] Mass (FAB): 569 (M⁺+1)

EXAMPLE 31(1)

[1627] Potassium salt ofN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(1-sulfoethyl)phenyl]ureawas prepared in a similar manner to that of Example 22(3).

[1628] mp: 246.9-249.1° C.

[1629] IR (Nujol, cm⁻¹): 1670, 1660

[1630]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 1.41 (1H, d, J=7.1Hz), 2.37(3H, s), 2.44 (3H, s), 3.0-3.4 (2H, m), 3.5-3.9 (3H, m), 3.96 (1H, d,J=16.5Hz), 5.12 (1H, d, J=16.5Hz), 5.0-5.2 (1H, m), 6.8-6.9 (1H, m),6.9-7.6 (7H. m), 8.9-9.0 (1H, m)

[1631] Mass (FAB): 634 (M⁺+1)

EXAMPLE 31(2)

[1632]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(2-methylpyridin-6-yl)ureawas prepared in a similar manner to that of Example 22(3).

[1633] mp: 150.8-152.1° C.

[1634] IR (Nujol, cm⁻¹): 1670

[1635] hu 1H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.36 (3H, s), 2.44 (3H,s), 2.42 (3H, s), 3.0-3.5 (2H, br), 3.5-3.9 (2H, m), 3.96 (1H, d,J=16.3Hz), 5.0-5.2 (2H, m), 6.7-7.7 (6H, m), 9.43 (1H, br, s)

[1636] Mass (APCI): 503 (M⁺+1)

EXAMPLE 31(3)

[1637]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(4-methylpyridin-2-yl)ureawas prepared in a similar manner to that of Example 22(3).

[1638] mp: 152.0-154.1° C.

[1639] IR (Nujol, cm⁻¹): 1680, 1660

[1640]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.24 (3H, s), 2.36 (3H, s),2.44 (3H, s), 2.44 (3H, s), 2.9-3.4 (2H, br), 3.5-3.9 (2H, m), 3.95 (1H,d, J=16.4Hz), 5.09 (1H, d, J=16.4Hz), 5.18 (1H, d, J=7.1Hz), 6.8 (1H,br), 7.0-7.6 (5H, m), 8.0-8.2 (1H, m), 9.39 (1H, br, s)

[1641] Mass (APCI): 503 (M⁺+1)

EXAMPLE 31(4)

[1642] A mixture of(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-3-(imidazol-1-yl)carbonylamino-2,3-dihydro-1H-1,4-benzodiazepin-2-one(300 mg), N,N-dimethyl-1,3-phenylenediamine dihydrochloride (149 mg) andtriethylamine (2 ml) in N,N-dimethylformamide (6 ml) was stirred at 100°C. for 2 hours. After allowing to cool to room temperature, ethylacetate and water were added to the reaction mixture under stirring. Theseparated organic layer was washed with water and brine, and then driedover sodium sulfate. The solvent was evaporated in vacuo to afford anamorphous powder, which was washed with diisopropyl ether and collectedby filtration to give a pale gray powder (320 mg). To the powderdissolved in 1,4-dioxane was added 4N-hydrogen chloride in 1,4-dioxane(0.5 ml) at ambient temperature under stirring. The resultant mixturewas evaporated in vacuo to dryness to afford a residue, which was washedwith diisopropyl ether and collected by filtration to giveN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(N,N-dimethylamino)phenyl]urea hydrochloride (280 mg, 67.1%yield).

[1643] mp: 190.9-193.1° C.

[1644] IR (Nujol, cm⁻¹): 1690, 1630

[1645]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.43 (3H, s), 2.73 (3H, s),2.86 (3H, s), 2.7-3.4 (2H, m), 3.6-4.0 (2H, m), 4.06 (1H, d, J=16.4Hz),5.23 (1H, d, J=16.4Hz), 5.61 (1H, d, J=6.2Hz), 6.7-7.0 (1H, m), 7.2-8.0(7H, m), 10.04(1H, br, s)

[1646] Mass (APCI): 531(free

M⁺+1)

EXAMPLE 32

[1647]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-one-4-oxide-3-yl]-N′-(3-methylephenyl)urea(45.3 mg) was treated with acetic anhydride (1.8 ml) at 50° C. for 5hours. After the reaction was completed, acetic anhydride was removedunder reduced pressure. The residue was subjected to preparative thinlayer chromatography on silica gel (60F₂₅₄, 0.5 mm, 20×20 cm; Merck)developed with a mixture of CHCl₃, AcOEt and MeOH (14:1:0.4) to giveN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl-2,3-dihydro-5-acetoxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureaas an amorphous mass (59.9 mg), which was powdered by triturated indiisopropyl ether and collected by filtration (26.5 mg; 59.3%).

[1648] mp: 133-134.5° C.

[1649]¹H-NMR(CDCl₃, δ): 1.50-2.17 (10H, m), 2.10 (3H, s), 2.29 (3H, s),2.38 (3H, s), 3.28-3.74 (4H, m), 4.62 (2H, d, d, J=15.6Hz, J=319.0Hz),5.17 (2H, d, d, J=9.45Hz, J=15.7Hz), 5.59 (1H, d, J=7.82Hz), 6.76-7.56(9H, m)

[1650] APCI-MS (m/z): 560.3 (M⁺+1)

EXAMPLE 33

[1651] To a solution of(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one(285 mg) in tetrahydrofuran (4 ml) was added dropwise 3-tolyl isocyanate(100 mg) under stirring at room temperature. The mixture was stirred atroom temperature for 2 hours. Removal of the solvent in vacuo afforded aresidue, which was triturated in diisopropyl ether and collected byfiltration to give a white powder. To a solution of the powder in ethylacetate was added 4N-hydrogen chloride in ethyl acetate (0.25 ml) undercooling. The mixture was evaporated in vacuo to dryness. The residue waswashed with diisopropyl ether and collected by filtration to affordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureahydrochloride (250 mg, 61.5%) as a crystalline powder.

[1652] mp: 216.5-218.7° C.

[1653] IR (Nujol, cm⁻¹): 1680, 1630

[1654]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.24 (3H, s), 2.80 (6H, br,s), 3.0-3.2 (1H, m), 3.2-3.4 (1H, m), 3.5-3.9 (2H, br, m), 4.56 (1H, d,J=16.7Hz), 5.11 (1H, d, J=16.7Hz), 5.67 (1H, m), 6.7-6.8 (1H, m),7.0-7.3 (3H, m), 7.4-7.7 (3H, m), 7.72 (1H, m), 9.56 (1H, br, s)

[1655] Mass (FAB): 531 (hydrochloride free M⁺+1)

EXAMPLE 34

[1656]N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-tert-butoxycarbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1657] mp: 151.4-174.2° C.(dec.)

[1658] IR (Nujol, cm⁻¹): 1745, 1650

[1659]¹H-NMR (DMSO-d₆, δ): 1.25 (9H, s), 2.46 (3H, s), 4.11 (1H, d,J=16.8Hz), 4.60 (1H, d, J=16.7Hz), 5.34 (1H, d, J=8.4Hz), 6.9-7.8 (10H,m), 8.1-8.3 (2H, m), 9.32 (1H, br, s)

[1660] Mass (APCI): 585 (M⁺+1)

EXAMPLE 35

[1661]N-[(3RS)-1-(Adamantan-1-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1662] mp: 195.0-218.4° C.(dec.)

[1663] IR (Nujol, cm⁻¹): 1650

[1664]¹H-NMR (DMSO-d₆, δ): 1.5-2.2 (15H, m), 2.42 (3H, br, s), 4.12 (1H,d, J=17.1Hz), 5.23 (1H, d, J=17.5Hz), 5.31 (1H, d, J=8.3Hz), 6.9-7.8(11H, m), 8.1 (1H, m), 9.28 (1H, br, s)

[1665] Mass (FAB): 647 (M⁺+1)

EXAMPLE 36

[1666]N-[(3RS)-2,3-Dihydro-1,5-9-trimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1667] mp: 204.2-206.6° C.

[1668] IR (Nujol, cm⁻¹): 1685, 1645, 1610

[1669]¹H-NMR (DMSO-d₆, δ): 2.22 (3H, s), 2.35 (3H, s), 2.42 (3H, s),3.10 (3H, s), 5.03 (1H, dd, J=1.4Hz, J=8.5Hz), 6.72 (1H, d, J=6.4Hz),7.0-7.7 (7H, m), 8.93 (1H, br, s)

[1670] Mass (APCI): 351 (M⁺+1)

EXAMPLE 37

[1671]N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1672] mp: 128.4-136.2° C.

[1673] IR (Nujol, cm⁻¹): 1650

[1674]¹H-NMR (DMSO-d₆, δ): 2.22 (3H, s), 2.27 (3H, s), 2.40 (3H, s),2.42 (3H, s), 4.55 (1H, d, J=17.1Hz), 5.12 (1H, d, J=8.5Hz), 5.37 (1H,d, J=17.2Hz), 6.7-6.8 (1H, m), 7.0-7.8 (11H, m), 8.86 (1H, br, s)

[1675] Mass (APCI): 469 (M⁺+1)

EXAMPLE 38

[1676]N-[(3RS)-1-(Adamantan-1-yl)carbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1677] mp: 182.2-184.2° C.

[1678] IR (Nujol, cm⁻¹): 1700, 1658, 1638

[1679]¹H-NMR (DMSO-d₆, δ): 1.6-2.1 (15H, m), 2.22 (3H, s), 2.34 (3H, s),3.96 (1H, d, J=17.5Hz), 5.0-5.1 (1H, m), 5.21 (1H, d, J=17.5Hz), 6.72(1H, d, J=6.3Hz), 7.1-7.7 (7H, m), 8.84 (1H, br, s)

[1680] Mass (APCI): 513 (M⁺+1)

EXAMPLE 39

[1681]N-[(3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1682] mp: 179.2-180.9° C.

[1683] IR (Nujol, cm⁻¹): 1710, 1655, 1638

[1684]¹H-NMR (DMSO-d₆, δ): 1.0-1.8 (10H, m), 1.8-2.0 (1H, m), 2.22 (3H,s), 2.33 (3H, s), 4.06 (1H, d, J=17.6Hz), 5.02 (1H, d, J=17.3Hz), 5.08(1H, d, J=7.0Hz), 6.72 (1H, d, J=6.0Hz), 7.0-7.6 (7H, m), 8.84 (1H, br,s)

[1685] Mass (APCI): 461 (M⁺+1)

EXAMPLE 40

[1686]N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-methylcarbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1687] mp: 173.5-189.8° C.

[1688] IR (Nujol, cm⁻¹): 1730, 1680, 1650

[1689]¹H-NMR (DMSO-d₆, δ): 2.03 (3H, s), 2.41 (3H, s), 4.29 (1H, d,J=17.7Hz), 4.96 (1H, d, J=17.6Hz), 6.9-7.8 (11H, m), 8.20 (1H, m), 9.35(1H, br, s)

[1690] Mass (APCI): 527 (M⁺+1)

EXAMPLE 41

[1691]N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-tert-butylcarbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea was prepared in a similar manner to that of Example 59.

[1692] mp: 179.6-181.2° C.

[1693] IR (Nujol, cm⁻¹): 1720, 1670, 1645

[1694]¹H-NMR (DMSO-d₆, δ): 1.08 (9H, s), 2.22 (3H, s), 2.34 (3H, s),4.01 (1H, d, J=17.4Hz), 5.08 (1H, dd, J=1.4Hz and J=8.5Hz), 5.22 (1H, d,J=17.4Hz), 6.72 (1H, d, J=6.5Hz), 7.0-7.7 (7H, m), 8.84 (1H, br, s)

[1695] Mass (APCI): 435 (M⁺+1)

EXAMPLE 42

[1696]N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-(3-nitrophenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1697] mp: 194.4-198.1° C.

[1698] IR (Nujol, cm⁻¹): 1655, 1620

[1699]¹H-NMR (DMSO-d₆, δ): 2.50 (3H, s), 4.96 (1H, d, J=17.7Hz), 5.43(1H, d, J=8.3Hz), 5.84 (1H, d, J=17.8Hz), 7.0-8.5 (15H, m), 8.65 (1H,m), 9.33 (1H, m)

[1700] Mass (APCI): 634 (M⁺+1)

EXAMPLE 43

[1701]N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-nitrophenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1702] mp: 192.2-197.1° C.

[1703] IR (Nujol, cm⁻¹): 1650, 1620

[1704]¹H-NMR (DMSO-d₆,δ): 2.45 (3H, s), 4.73 (1H, d, J=18.1Hz), 5.3-5.5(2H, m), 7.0-8.2 (16H, m)

EXAMPLE 44

[1705]N-[(3RS)-2,3-Dihydro-1-ethylcarbonylmethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1706] mp: 125.1-127.5° C.

[1707] IR (Nujol, cm⁻¹): 1720, 1640

[1708]¹H-NMR (DMSO-d₆, δ): 0.87 (3H, t, J=7.2Hz), 2.22 (3H, s), 2.33(3H, s), 2.3-2.5 (2H, m), 4.08 (1H, d, J=17.5Hz), 4.92 (1H, d,J=17.5Hz), 5.10 (1H, dd, J=1.4Hz and 8.5Hz), 6.7-6.9 (1H, m), 7.0-7.7(7H, m), 8.90 (1H, br, s)

[1709] Mass (APCI): 407 (M⁺+1)

EXAMPLE 45

[1710]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1711] mp: 189.9-192.8° C.

[1712] IR (Nujol, cm⁻¹): 1650, 1610, 1700

[1713]¹H-NMR (DMSO-d₆, δ): 1.11 (3H, d, J=7.0Hz), 1.21 (3H, d, J=6.5Hz),1.4-2.1 (10H, m), 2.22 (3H, s), 2.37 (3H, s), 3.0-3.4 (2H, m), 3.6-4.0(2H, m), 4.04 (1H, d, J=16.1Hz), 5.00 (1H, d, J=16.2Hz), 5.09 (1H, d,J=8.4Hz), 6.72 (1H, d, J=6.2Hz), 7.0-7.7 (7H, m), 8.85(1H, br, s)

[1714] Mass (APCI): 530 (M⁺+1)

EXAMPLE 46

[1715]N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-methylcarbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1716] mp: 126.1-127.7° C.

[1717] IR (Nujol, cm⁻¹): 1720, 1650

[1718]¹H-NMR (DMSO-d₆, δ): 2.00 (3H, s), 2.22 (3H, s), 2.33 (3H, s),2.47 (3H, s), 4.11 (1H, d, J=17.8Hz), 4.93 (1H, d, J=17.6Hz), 5.0-5.2(1H, m), 6.7-6.8 (1H, m), 7.0-7.6 (7H, m), 8.90 (1H, br, s)

[1719] Mass (APCI): 393 (M⁺+1)

EXAMPLE 47

[1720]N-[(3RS)-5-Cyclohexyl-1-cyclopropylcarbony]methyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1721] mp: 227.1-233.2° C.

[1722] IR (Nujol, cm⁻¹): 1715, 1650

[1723]¹H-NMR (DMSO-d₆, δ): 0.7-2.1 (15H, m), 2.36 (3H, s), 2.8-3.0 (1H,m), 4.30 (1H, d, J=17.6Hz), 4.96 (1H, d, J=17.5Hz), 5.10 (1H, d,J=8.2Hz), 7.3-7.7 (7H, m), 8.15 (1H, br), 9.23 (1H, br, s)

[1724] Mass (APCI): 541 (M⁺+1)

EXAMPLE 48-1

[1725]N-[(3RS)-2,3-Dihydro-1-ethoxycarbonylmethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1726] mp: 229.7-231.0° C.

[1727] IR (Nujol, cm⁻¹): 1755, 1685, 1645, 1615

[1728]¹H-NMR (DMSO-d₆, δ): 1.27 (3H, t, J=7.1Hz), 2.22 (3H, s), 2.33(3H, s), 2.45 (3H, s), 4.02 (2H, q, J=7.1Hz), 4.08 (1H, m), 4.68 (1H, d,J=16.8Hz), 5.09-5.14 (1H, m), 6.72 (1H, d, J=6.4Hz), 7.0-7.7 (7H, m),8.87 (1H, br, s)

[1729] Mass (APCI): 423 (M⁺+1)

EXAMPLE 48-2

[1730] A mixture of N-[(3RS)-2,3-dihydro-1-ethoxycarbonymethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (1.3g) and 1N aqueous sodium hydroxide (15 ml) in 1,2-dimethoxyethane (15ml) was stirred at room temperature overnight. 1N aqueous hydrochloricacid was added to the reaction mixture. The mixture was evaporated todryness to afford a residue, which was triturated in water and collectedby filtration to give the first crop of the desired product as a whitepowder (417 mg, 34.3%). To the filtrate were added ethyl acetate and0.1N aqueous hydrochloric acid. The separated organic layer was washedwith water and brine, and then dried over magnesium sulfate. The solventwas evaporated in vacuo to afford the second crop ofN-[(3RS)-2,3-dihydro-1-carboxymethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(631 mg, 51.9%) as a white crystalline powder.

[1731] IR (Nujol, cm⁻¹) 1690, 1658, 1620

[1732] Anal: C₂₁H22N₄O₄·0.5H₂O

[1733] calc. C: 62.52, H: 5.75, N: 13.89

[1734] found C: 62.86, H: 5.58, N: 13.84

[1735]¹H-NMR (DMSO-d₆, δ): 2.22 (3H, s), 2.33 (3H, s), 2.41 (3H, s),3.94 (1H, d, J=17.0Hz), 4.65 (1H, d, J=17.0Hz), 5.10 (1H, d, J=7.2Hz),6.72 (1H, d, J=6.4Hz), 7.0-7.6 (7H, m), 8.91 (1H, s)

[1736] Mass (APCI): 395 (M⁺+1)

EXAMPLE 48-3(1)

[1737]N-[(3RS)-1-[4-(Piperidino)piperidin-1-yl]carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1738] mp: 214.5-217.3° C.

[1739] IR (Nujol, cm⁻¹): 1660

[1740]¹H-NMR (DMSO-d₆, δ): 1.0-1.9 (10H, m), 2.22 (3H, s), 2.35 (3H, s),2.43 (3H, s), 2.3-2.6 (6H, m), 2.8-3.1 (1H, m), 3.7-4.0 (2H, m), 4.1-4.3(1H, m), 4.9-5.2 (2H, m), 6.71 (1H, d, J=6.4Hz), 7.0-7.7 (7H, m), 8.92(1H, br, s)

[1741] Mass (APCI): 545 (M⁺+1)

EXAMPLE 48-3(2)

[1742]N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-(4-methylpiperazin-1-yl)carbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1743] IR (Nujol, cm⁻¹): 1675, 1640, 1610

[1744]¹H-NMR (DMSO-d₆, δ): 2.15 (3H, s), 2.22 (3H, s), 2.35 (3H, s),2.43 (3H, s), 3.3-3.5 (4H, br), 3.91 (1H, d, J=16.4Hz), 5.04 (1H, d,J=16.1Hz), 5.11-5.12 (1H, m), 6.71 (1H, d, J=6.3Hz), 7.0-7.6 (7H, m),8.92 (1H, br, s)

[1745] Mass (APCI): 477 (M⁺+1)

EXAMPLE 48-3(3)

[1746]N-[(3RS)-5,9-Dimethyl-1-[(pyrrolidin-1-yl)carbonylmethyl]-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1747] IR (Nujol, cm⁻¹) 1650

[1748]¹H-NMR (DMSO-d₆, δ): 1.6-2.0 (2H, m), 2.22 (3H, s), 2.35 (3H, s),2.43 (3H, s), 3.1-3.3 (2H, m), 3.88 (1H, d, J=16.4Hz), 4.86 (1H, d,J=16.4Hz), 5.10 (1H, d, J=7.2Hz), 6.72 (1H, d, J=6.3Hz), 7.0-7.6 (7H,m), 8.92 (1H, s)

[1749] Mass (APCI): 448 (M⁺+1)

EXAMPLE 48-3(4)

[1750]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1751] IR (Nujol, cm⁻¹): 1650, 1610

[1752]¹H-NMR (DMSO-d₆, δ): 1.2-1.8 (10H, m), 2.22 (3H, s), 2.36 (3H, s),2.44 (3H, s), 2.9-3.3 (2H, m), 3.3-3.6 (2H, m), 3.93 (1H, d, J=16.1Hz),4.95 (1H, d, J=16.1Hz), 5.09 (1H, d, J=7.1Hz), 6.71 (1H, d, J=6.5Hz),7.0-7.6 (7H, m), 8.86 (1H, br, s)

[1753] Mass (APCI): 490 (M⁺+1)

EXAMPLE 48-3(5)

[1754]N-{(3RS)-1-[(3RS)-3-(N,N-Diethylaminocarbonyl)piperidin-1-yl]-carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl}-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1755] mp: 150.8-154.7° C.

[1756] IR (Nujol, cm⁻¹): 1655, 1610

[1757]¹H-NMR (DMSO-d₆, δ): 0.9-1.3 (8H, m), 1.4-2.0 (2H, m), 2.22 (3H,s), 2.35 (3H, s), 2.43 (3H, s), 2.9-3.5 (7H, m), 3.7-4.3 (3H, m),5.0-5.2 (2H, m), 6.71 (1H, d, J=6.2Hz), 7.0-7.8 (7H, m), 8.90 (1H, m)

[1758] Mass (APCI): 561 (M⁺+1)

EXAMPLE 48-3(6)

[1759]N-[(3RS)-1-(4-Hydroxy-4-phenylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1760] mp: 163.2-164.9° C.

[1761] IR (Nujol, cm⁻¹): 1665, 1645

[1762]¹H-NMR (DMSO-d₆, δ): 1.4-2.0 (4H, m), 2.22 (3H, s), 2.37 (3H, s),2.45 (3H, s), 2.8-3.0 (1H, m), 3.2-3.6 (2H, m), 3.6-4.3 (3H, m), 4.9-5.2(2H, m), 6.71 (1H, d, J=6.5Hz), 7.0-7.6 (12H, m), 8.94 (1H, m)

[1763] Mass (APCI): 554 (M⁺+1)

EXAMPLE 48-3(7)

[1764]N-[(3RS)-2,3-dihydro-5,9-dimethyl-1-(morpholin-1-yl)-carbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1765] mp: 219.0-220.1° C.

[1766] IR (Nujol, cm⁻¹): 1675, 1640

[1767]¹H-NMR (DMSO-d₆, δ): 2.22 (3H, s), 2.36 (3H, s), 2.43 (3H, s),3.3-3.6 (8H, m), 3.94 (1H, d, J=16Hz), 5.04 (1H, d, J=16Hz), 5.10 (1H,d, J=6.9Hz), 6.72 (1H, d, J=6.3Hz), 7.0-7.6 (7H, m), 8.92 (1H, s)

[1768] Mass (APCI): 464 (M⁺+1)

EXAMPLE 48-3(8)

[1769]N-{(3RS)-2,3-Dihydro-5,9-dimethyl-1-[4-methylpiperazin-1-yl)carbonylmethyl]-2-oxo-1H-1,4-benzodiazepin-3-yl}-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1770] IR (Nujol, cm⁻¹): 1675, 1640, 1610

[1771]¹H-NMR (DMSO-d₆, δ): 2.15 (3H, s), 2.22 (3H, s), 2.35 (3H, s),2.43 (3H, s), 3.3-3.5 (4H, br), 3.91 (1H, d, J=16.4Hz), 5.04 (1H, d,J=16.1Hz), 5.11-5.12 (1H, m), 6.71 (1H, d, J=6.3Hz), 7.0-7.6 (7H, m),8.92 (1H, br, s)

[1772] Mass (APCI): 477 (M⁺+1)

EXAMPLE 48-3(9)

[1773]N-[(3RS)-1-(N,N-Diethylamino)carbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1774] IR (Nujol, cm⁻¹): 1670, 1625

[1775]¹H-NMR (DMSO-d₆, δ): 0.92 (3H, t, J=7.0Hz), 1.13 (3H, t, J=7.0Hz),2.22 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 3.0-3.5 (4H, m), 3.88 (1H, d,J=16.1Hz), 4.97 (1H, d, J=16.1Hz), 5.08 (1H, d, J=7.1Hz), 6.71 (1H, d,J=6.5Hz), 7.0, 7.6 (7H, m), 8.89 (1H, br, s)

[1776] Mass (APCI): 450 (M⁺+1)

EXAMPLE 48-3(10)

[1777]N-[(3RS)-2,3-Dihydro-1-(N-ethylamino)carbonylmethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1778] IR (Nujol, cm⁻¹): 1658, 1610

[1779]¹H-NMR (DMSO-d₆, δ): 0.93 (3H, t, J=7.2Hz), 2.22 (3H, s), 2.32(3H, s), 2.42 (3H, s), 2.9-3.0 (2H, m), 3.76 (1H, d, J=15.8Hz), 4.63(1H, d, J=15.8Hz), 5.07 (1H, d, J=8.5Hz), 6.71 (1H, d, J=6.2Hz), 7.0-7.3(3H, m), 7.3-7.4 (1H, m), 7.4-7.6 (2H, m), 7.8-8.0 (1H, m), 8.91 (1H,br, s)

[1780] Mass (APCI): 422 (M⁺+1)

EXAMPLE 48-3(11)

[1781]N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-(N-tert-butylaminocarbonylmethyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1782] mp: 243.4-244.4° C.

[1783] IR (Nujol, cm⁻¹): 3310, 1645

[1784]¹H-NMR (DMSO-d₆, δ): 1.13 (9H, s), 2.22 (3H, s), 2.32 (3H, s),2.43 (3H, s), 3.68 (1H, d, J=15.7Hz), 4.62 (1H, d, J=15.7Hz), 5.07 (1H,dd, J=1.4Hz and 8.6Hz), 6.72 (1H, d, J=6.5Hz), 7.0-7.6 (7H, m), 8.87(1H, br, s)

[1785] Mass (APCI): 450 (M⁺+1)

EXAMPLE 48-3(12)

[1786]N-[(3RS)-1-(Azacycloheptan-1-yl)carbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1787] mp: 203.6-204.2° C.

[1788] IR (Nujol, cm⁻¹): 1670, 1630

[1789]¹H-NMR (DMSO-d₆, δ): 1.3-1.9 (8H, m), 2.22 (3H, s), 2.36 (3H, s),2.44 (3H, s), 3.0-3.2 (1H, m), 3.2-3.4 (1H, m), 3.4-3.7 (2H, m), 3.92(1H, d, J=16.2Hz), 4.96 (1H, d, J=16.1Hz), 5.09 (1H, d, J=7.4Hz), 6.71(1H, d, J=6.4Hz), 7.0-7.6 (7H, m), 8.87 (1H, br, s)

[1790] Mass (APCI): 476 (M⁺+1)

EXAMPLE 48-3(13)

[1791]N-[(3RS)-1-(4-Aminocarbonylpiperidin-1-yl)carbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1792] mp: 196.8-198.0° C.

[1793] IR (Nujol, cm⁻¹): 1650

[1794]¹H-NMR (DMSO-d₆, δ): 1.1-1.8 (4H, m), 2.22 (3H, s), 2.36 (3H, s),2.43 (3H, s), 2.6-2.8 (1H, m), 2.8-3.2 (2H, m), 3.7-4.2 (3H, m), 4.9-5.2(2H, m), 6.7-6.9 (1H, br, s), 7.0-7.6 (7H, m), 8.93 (1H, br, s)

[1795] Mass (APCI): 505 (M⁺+1)

EXAMPLE 48-3(14)

[1796]N-[(3RS)-2,3-Dihydro-1-[4-(2-hydroxyethyl)piperazin-1-yl]carbonylmethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1797] mp: 221.7-224.2° C.

[1798] IR (Nujol, cm⁻¹): 1660, 1635

[1799]¹H-NMR (DMSO-d₆, δ): 2.22 (3H, s), 2.35 (3H, s), 2.43 (3H, s),2.2-2.6 (8H, m), 3.3-3.6 (4H, m), 3.91 (1H, d, J=16.4Hz), 4.3-4.5 (1H,m), 5.0-5.2 (2H, m), 6.73 (1H, m), 7.0-7.6 (7H, m), 8.92 (1H, br, s)

[1800] Mass (APCI): 507 (M⁺+1)

EXAMPLE 48-3(15)

[1801]N-[(3RS)-2,3-Dihydro-1-(N,N-diisobutylamino)carbonylmethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1802] mp: 226.9-228.1° C.

[1803] IR (Nujol, cm⁻¹): 1680, 1660

[1804]¹H-NMR (DMSO-d₆, δ): 0.7-0.8 (6H, m), 0.8-1.0 (6H, m), 2.22 (3H,s), 2.36 (3H, s), 2.43 (3H, s), 2.9-3.2 (4H, m), 3.89 (1H, d, J=16.0Hz),4.99 (1H, d, J=16.0Hz), 5.07 (1H, d, J=7.1Hz), 6.71 (1H, d, J=6.3Hz),7.0-7.6 (7H, m), 8.85 (1H, br, s)

[1805] Mass (APCI): 506 (M⁺+1)

EXAMPLE 48-3(16)

[1806]N-[(3RS)-2,3-Dihydro-1-(N,N-bis-(2-hydroxyethyl)amino)-carbonylmethy]-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

[1807] mp: 160.5-161.1° C.

[1808] IR (Nujol, cm⁻¹): 1650, 3300

[1809]¹H-NMR (DMSO-d₆, δ): 2.22 (3H, s), 2.34 (3H, s), 2.43 (3H, s),2.9-3.8 (6H, m), 4.15 (1H, d, J=16.5Hz), 4.5-4.7 (1H, m), 4.8-5.0 (1H,br), 5.0-5.2 (2H, br), 6.72 (1H, d, J=6.3Hz), 7.0-7.6 (7H, m), 8.92 (1H,br, s)

[1810] Mass (APCI): 482 (M⁺+1)

EXAMPLE 49

[1811]N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1-(imidazol-4-yl)methyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]ureawas prepared in a similar manner to that of Example 51.

[1812] mp: 168.2-179.2° C.

[1813] IR (Nujol, cm⁻¹): 1650

[1814]¹H-NMR (DMSO-d₆, δ): 0.9-1.9 (10H, m), 2.45 (3H, s), 2.73 (1H, br,s), 4.23 (1H, d, J=14.7Hz), 5.03 (1H, d, J=8.3Hz), 5.36 (1H, d,J=14.7Hz), 6.8-7.0 (1H, br, s), 7.2-7.6 (8H, m), 8.0-8.2 (2H, m), 9.25(1H, br, s)

[1815] Mass (FAB): 539 (M⁺+1)

EXAMPLE 50(1)

[1816]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-bromophenyl)ureawas prepared in a similar manner to that of Example 59.

[1817] mp: 168.1-171.1° C.

[1818] IR (Nujol, cm⁻¹): 1645

[1819]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.36 (3H, s), 2.45 (3H, s),2.9-3.4 (2H, m), 3.5-3.9 (2H, m), 3.96 (1H, d, J=16.5Hz), 5.11 (1H, d,J=16.5Hz), 5.09 (1H, d, J=8.6Hz), 7.0-7.6 (7H, m), 7.75 (1H, br, s),9.16 (1H, br, s)

[1820] Mass (APCI): 568 (M⁺+2), 564 (M⁺)

EXAMPLE 50(2)

[1821]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-chlorophenyl)ureawas prepared in a similar manner to that of Example 59.

[1822] mp: 181.2-185.1° C.

[1823] IR (Nujol, cm⁻¹): 1680, 1640

[1824]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.36 (3H, s), 2.44 (3H, s),2.9-3.3 (2H, m), 3.5-3.9 (2H, m), 3.96 (1H, d, J=16.4Hz), 5.11 (1H, d,J=16.4Hz), 5.0-5.2 (1H, m), 6.94 (1H, d, J=8.5Hz), 7.0-7.7 (7H, m), 9.17(1H, br, s)

[1825] Mass (APCI): 522 (M⁺+1)

EXAMPLE 50(3)

[1826]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylthiophenyl)ureawas prepared in a similar manner to that of Example 59.

[1827] mp: 237.2-238.5° C.

[1828] IR (Nujol, cm⁻¹): 1680, 1660, 1645

[1829]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.36 (3H, s), 2.40 (3H, s),2.44 (3H, s), 2.9-3.4 (2H, m), 3.5-3.9 (2H, m), 3.96 (1H, d, J=16.5Hz),5.11 (1H, d, J=16.5Hz), 5.0-5.2 (1H, m)

[1830] Mass (APCI): 534 (M⁺+1)

EXAMPLE 50(4)

[1831]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methoxyphenyl)ureawas prepared in a similar manner to that of Example 59.

[1832] mp: 169.6-170.7° C.

[1833] IR (Nujol, cm⁻¹): 1700, 1675, 1640

[1834]¹H-NMR (DMSO-d₆, δ): 1.3-2.2 (10H, m), 2.36 (3H, s), 2.44 (3H, s),2.9-3.3 (2H, m), 3.5-3.9 (2H, m), 3.67 (3H, s), 3.96 (1H, d, J=16.5Hz),5.11 (1H, d, J=16.5Hz), 5.0-5.2 (1H, m), 6.4-6.6 (1H, m), 6.7-6.9 (1H,m), 7.0-7.6 (6H, m), 8.98 (1H, br, s)

[1835] Mass (APCI): 518 (M⁺+1)

EXAMPLE 50(5)

[1836]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1837] mp: 176.9-179.1° C.

[1838] IR (Nujol, cm⁻¹): 1670, 1640

[1839]¹H-NMR (DMSO-d₆, δ): 1.4-1.8 (8H, m), 1.9-2.1 (2H, m), 2.22 (3H,s), 2.36 (3H, s), 2.44 (3H, s), 3.0-3.4 (2H, m), 3.6-4.0 (2H, m), 3.96(1H, d, J=16Hz), 5.11 (1H, d, J=16Hz), 5.0-5.1 (1H, br, m), 6.71 (1H, d,J=6.6Hz), 7.0-7.6 (7H, m), 8.87 (1H, br, s)

[1840] Mass (APCI): 502 (M⁺+1)

EXAMPLE 51

[1841] A mixture of3-amino-1-(2-acetylbenzyl)-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one(280 mg), 4-nitrophenyl N-{3-(tetrazol-5-yl)phenyl}carbamate (249 mg)and triethylamine (281 mg) in NN-dimethylformamide was stirred at roomtemperature for 50 minutes. Ethyl acetate and 0.1N aqueous hydrochloricacid were added to the reaction mixture. The separated organic layer waswashed with water and brine, and then dried over magnesium sulfate. Thesolvent was evaporated in vacuo to afford a residue, which was washedwith diisopropyl ether to give.N-[(3RS)-1-(2-acetylbenzyl)-5-cyclohexyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea(348 mg, 84.9%) as a crystalline powder.

[1842] mp: 199.0-208.0° C.

[1843] IR (Nujol, cm⁻¹): 1635

[1844]¹H-NMR (DMSO-d₆, δ): 1.0-2.2 (1H, m), 2.33 (3H, s), 2.41 (3H, s),3.00 (1H, br, s), 4.57 (1H, d, J=17.4Hz), 5.19 (1H, d, J=8.1Hz), 5.33(1H, d, J=17.4Hz), 7.0-8.0 (11H, m), 9.22 (1H, br, s)

[1845] Mass (APCI): 591 (M⁺+1)

EXAMPLE 52

[1846]N-[(3RS)-5-(3-Azabicyclo[3.2.2]non-3-yl)methyl-2,3-dihydro-1,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1847] mp: 145.6-149.2° C.

[1848] IR (Nujol, cm⁻¹): 1670, 1635, 1600

[1849]¹H-NMR (DMSO-d₆, δ): 1.1-1.6 (8H, m), 1.6-1.8 (2H, m), 2.22 (3H,br, s), 2.35 (3H, s), 3.06 (3H, s), 3.06-3.10 (1H, m), 4.23 (1H, d,J=13.8Hz), 5.12 (1H, d, J=7.9Hz), 6.72 (1H, d, J=6.3Hz), 7.0-7.3 (3H,m), 7.3-7.45 (2H, m), 7.45-7.6 (1H, d, J=6.9Hz), 7.67 (1H, d, J=7.5Hz),8.94 (1H.s)

[1850] Mass (APCI): 474 (M⁺+1)

EXAMPLE 53

[1851]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-methoxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1852] mp: 178.1-182.1° C.

[1853] IR (Nujol, cm⁻¹): 1640

[1854]¹H-NMR (DMSO-d₆, δ): 1.4-1.9 (8H, m), 1.9-2.1 (2H, m), 2.22 (3H,s), 2.38 (3H, s), 3.35 (3H, s), 3.3-4.1 (4H, m), 4.00 (1H, d, J=16.9Hz),4.52 (2H, m), 5.0-5.3 (2H, m), 6.74 (1H, br, s), 7.0-7.7 (7H, m), 8.88(1H, br, s)

[1855] Mass (APCI): 532 (M⁺+1)

EXAMPLE 54

[1856]N-[(3RS)-5-Cyclohexyl-1-cyclohexylcarbonylmethyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1857] mp: 159.3-169.6° C.

[1858] IR (Nujol, cm⁻¹): 1710, 1640, 1600

[1859]¹H-NMR (DMSO-d₆, δ): 1.0-2.1 (20H, m), 2.22 (3H, s), 2.33 (3H, s),2.3-2.6 (1H, br, s), 2.94 (1H, br, s), 4.10 (1H, d, J=17.4Hz), 4.89 (1H,d, J=17.4Hz), 5.06 (1H, d, J=8.4Hz), 6.71 (1H, d, J=5.5Hz), 7.0-7.6 (7H,m), 8.81 (1H, br, s)

[1860] Mass (APCI): 530 (M⁺+1)

EXAMPLE 55

[1861]N-[(3RS)-2,3-Dihydro-1,9-dimethyl-5-(4-methylpiperazin-1-yl)-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1862] mp: 136.2-140.1° C.

[1863] IR (Nujol, cm⁻¹): 1650, 1600

[1864]¹H-NMR (DMSO-d₆, δ): 2.07 (3H, s), 2.21 (3H, s), 2.27 (3H, s),2.35 (3H, s), 2.0-2.6 (4H, m), 2.9-3.2 (5H, m), 4.11 (1H, d, J=11.6Hz),5.07 (1H, d, J=8.1Hz), 6.7-6.9 (1H, br, s), 7.0-7.8 (7H, m)

[1865] Mass (APCI): 449 (M⁺+1)

EXAMPLE 56

[1866]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(N,N-dimethyaminomethyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1867] mp: 154.0-156.9° C.

[1868] IR (Nujol, cm⁻¹): 1650, 1610

[1869]¹H-NMR (DMSO-d₆, δ): 1.4-1.8 (8H, m), 1.9-2.1 (2H, m), 2.22 (3H,br, s), 2.25 (6H, br, s), 2.37 (3H, br, s), 3.0-3.2 (1H, m), 3.4-3.9(5H, m), 3.9-4.1 (1H, m), 4.9-5.1 (1H, m), 5.13 (1H, d, J=8.0Hz), 6.73(1H, m), 7.0-7.2 (2H, m), 7.2-7.4 (2H, m), 7.4-7.5 (1H, m), 7.8-7.9 (1H,m), 8.88 (1H, br, s)

[1870] Mass (APCI): 545

EXAMPLE 57

[1871]N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclopropyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1872] mp: 172.0-174.4° C.

[1873] IR (Nujol, cm⁻¹): 1680, 1650, 1610

[1874]¹H-NMR (DMSO-d₆, δ): 0.7-0.9 (2H, m), 0.9-1.3 (2H, m), 1.4-1.9(8H, m), 1.9-2.2 (3H, m), 2.22 (3H, s), 3.38 (3H, s), 3.1-3.4 (2H, m),3.6-3.9 (2H, m), 4.00 (1H, d, J=16Hz), 5.04 (1H, d, J=16Hz), 5.06 (1H,d, J=8.5Hz), 6.71 (1H, d, J=5.6Hz), 7.0-7.3 (4H, m), 7.3-7.45 (1H, m),7.45-7.6 (1H, m), 7.6-7.8 (1H, m), 8.82 (1H, br, s)

[1875] Mass (APCI): 528 (M⁺+1)

EXAMPLE 58

[1876]N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isobutyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Example 59.

[1877] mp: 133.6-135.4° C.

[1878] IR (Nujol, cm⁻¹): 1650, 1610

[1879]¹H-NMR (DMSO-d₆, δ): 0.94 (6H, d, J=6.6Hz), 1.4-1.9 (8H, m),1.9-2.1 (2H, m), 2.22 (3H, br, s), 3.37 (3H, br, s), 2.1-2.2 (1H, m),2.6-2.8 (2H, m), 3.0-3.2 (1H, m), 3.5-4.0 (3H, m), 4.01 (1H, d, J=16Hz),5.00 (1H, d, J=16Hz), 5.11 (1H, d, J=8.6Hz), 6.73 (1H, m), 7.0-7.6 (7H,m), 8.85 (1H, br, s)

[1880] Mass (APCI): 544 (M⁺+1)

EXAMPLE 59

[1881] A mixture of(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one(310 mg) and 3-methylphenyl isocyanate (113 mg) in tetrahydrofuran (8ml) was stirred at room temperature for 1 hour. The reaction mixture wasevaporated in vacuo to dryness. The residue was triturated indiisopropyl ether and collected by filtration to affordN-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl2,3-dihydro-5-ethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(360 mg, 86.2% yield) as a crystalline powder.

[1882] mp: 130.1-133.0° C.

[1883] IR (Nujol, cm⁻¹): 1650, 1610

[1884]¹H-NMR (DMSO-d₆, δ): 1.26 (3H, t, J=7.3Hz), 1.4-1.9 (8H, m),1.9-2.1 (2H, m), 2.22 (3H, s), 2.37 (3H, s), 2.7-3.0 (2H, m), 3.0-3.4(2H, m), 3.7-3.9 (2H, m), 3.98 (1H, d, J=16.2Hz), 5.08 (1H, d,J=16.0Hz), 5.14 (1H, d, J=7.7Hz), 6.71 (1H, d, J=6.5Hz), 7.0-7.6 (7H,m), 8.86 (1H, br, s)

[1885] Mass (APCI): 516 (M⁺+1)

EXAMPLE 60(1)

[1886]N-[(3RS)-1-(Piperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(2)

[1887]N-[(3RS)-1-(cis-2,6-Dimethylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(3)

[1888]N-[(3RS)-1-((2RS)-2-Hydroxymethylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(4)

[1889]N-[(3RS)-1-((3RS)-3-Carbamoylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(5)

[1890]N-[(3RS)-1-((3RS)-3-Hydroxymethylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(6)

[1891]N-[(3RS)-1-(4-Hydroxypiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(7)

[1892]N-[(3RS)-1-(4-Oxopiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(8)

[1893]N-[(3RS)-1-(4-Phenylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(9)

[1894]N-[(3RS)-1-(4-Benzylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(10)

[1895]N-[(3RS)-1-(4-Acetylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that Preparation 59-5.

EXAMPLE 60(11)

[1896]N-[(3RS)-1-(N,N-Diisopropylamino)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(12)

[1897]N-[(3RS)-1-(2-Hydroxyethylamino)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(13)

[1898]N-[(3RS)-1-(1-Methyl-1-phenylethylamino)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(14)

[1899]N-[(3RS)-1-(2-(2-Hydroxyethyl)piperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(15)

[1900]N-[(3RS)-1-(N,N-Diisobutylamino)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(16)

[1901]N-[(3RS)-1-(4-Phenylpiperazin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(17)

[1902]N-{(3RS)-1-[4-[(Pyrrolidin-1-yl)carbonylmethyl]piperazin-1-yl]carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl}-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(18)

[1903]N-{(3RS)-1-[4-(Pyridin-2-yl]piperazin-1-ylcarbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl}-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 60(19)

[1904]N-{(3RS)-1-[4-(Pyrimidin-2-yl)piperazin-1-yl]carbonylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl}-N′-(3-methylphenyl)ureawas prepared in a similar manner to that of Preparation 59-5.

EXAMPLE 61

[1905]N-[(3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl-N′-(3-methylphenyl)urcawas obtained in a similar manner to that of Example 59.

[1906] mp: 161.2-164.0° C.

[1907] IR (Nujol, cm⁻¹): 3350, 1730, 1680, 1650

[1908]¹H-NMR (DMSO-d₆, δ): 1.0-1.4 (8H, m), 1.5-2.0 (5H, m), 2.22 (3H,s), 2.35 (3H, s), 2.2-2.5 (1H, m), 2.8-3.1 (2H, m), 4.11 (1H, d,J=17.6Hz), 5.04 (1H, d, J=17.6Hz), 5.21 (1H, d, J=7.4Hz), 6.72 (1H, d,J=6.6Hz), 7.0-7.7 (7H, m), 8.99 (1H, s)

[1909] Mass (APCI)(e/z): 475 (M⁺+1)

EXAMPLE 62

[1910]N-[(3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-5-isopropyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1911] mp: 142.4-146.1° C.

[1912] IR (Nujol, cm⁻¹): 3320, 1730, 1680, 1650

[1913]¹H-NMR (DMSO-d₆, δ): 1.09 (3H, d, J=7.7Hz), 1.22 (3H, d, J=6.5Hz),1.0-1.4 (5H, m), 1.5-1.8 (4H, m), 1.8-2.0 (1H, m), 2.22 (3H, s), 2.34(3H, s), 2.3-2.5 (1H, m), 3.2-3.5 (1H, m), 4.11 (1H, d, J=17.4Hz), 4.94(1H, d, J=17.4Hz), 5.08 (1H, d, J=7.8Hz), 6.6-6.8 (1H, m), 7.0-7.6 (7H,m), 8.84 (1H, s)

[1914] Mass (APCI)(e/z): 489 (M⁺+1)

EXAMPLE 63

[1915]N-[(3RS)-1-Cycloheptylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1916] mp: 171.3-174.6° C.

[1917] IR (Nujol, cm⁻¹): 3360, 1720, 1660, 1640

[1918]¹H-NMR (DMSO-d₆, δ): 1.2-2.0 (2H, m), 2.22 (3H, s), 2.33 (3H, s),2.4-2.7 (1H, m), 4.09 (1H, d, J=18Hz), 5.00 (1H, d, J=18Hz), 5.06 (1H,d, J=8.3Hz), 6.7-6.8 (1H, m), 7.0-7.7 (7H, m), 8.86 (1H, s)

[1919] Mass (APCI)(e/z): 475 (M⁺+1)

EXAMPLE 64

[1920]N-[(3RS)-1-Cyclohexylcarbonylmethyl-5-cyclopropyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1921] mp: 143.6-144.2° C.

[1922] IR (Nujol, cm⁻¹): 3370, 1720, 1680, 1650

[1923]¹H-NMR (DMSO-d₆, δ): 0.8-1.4 (9H, m), 1.5-2.0 (5H, m), 2.1-2.5(2H, m), 2.22 (3H, s), 2.34 (3H, s), 2.8-3.0 (1H, m), 4.09 (1H, d,J=17Hz), 4.94 (1H, d, J=17Hz), 5.06 (1H, d, J=8.3Hz), 6.7-6.8 (1H, m),7.0-7.8 (7H, m), 8.8-9.0 (1H, m)

[1924] Mass (APCI)(e/z): 487 (M⁺+1)

EXAMPLE 65

[1925]N-[(3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1926] mp: 150.1-155.5° C.

[1927] IR (Nujol, cm⁻¹): 3280, 1720, 1670, 1645

[1928]¹H-NMR (DMSO-d₆, δ): 1.4-1.9 (8H, m), 2.22 (3H, s), 2.33 (3H, s),2.47 (3H, s), 2.8-3.0 (1H, m), 4.10 (1H, d, J=17.5Hz), 4.97 (1H, d,J=17.5Hz), 5.08 (1H, m), 6.7-6.8 (1H, m), 7.0-7.7 (7H, m), 8.86 (1H, s)

[1929] Mass (APCI)(e/z): 447 (M⁺+1)

EXAMPLE 66

[1930]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1931] mp: 189.0-189.5° C.

[1932] IR (Nujol, cm⁻¹): 3350, 1690, 1630

[1933]¹H-NMR (DMSO-d₆, δ): 1.23 (3H, t, J=7.3Hz), 1.3-1.9 (10H, m), 2.22(3H, s), 2.36 (3H, s), 2.7-2.95 (2H, m), 2.95-3.35 (2H, m), 3.35-3.60(2H, m),3.15 (1H, d, J=16.0Hz), 4.94 (1H, d, J=16.0Hz), 5.13 (1H, d,J=8.5Hz), 6.71 (1H, d, J=6.4Hz), 7.0-7.6 (6H, m), 8.83 (1H, s)

[1934] Mass (APCI)(e/z): 504 (M⁺+1)

EXAMPLE 67

[1935]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1936] mp: 131.7-132.8° C.

[1937] IR (Nujol, cm⁻¹): 3320, 1685, 1645, 1605

[1938]¹H-NMR (DMSO-d₆, δ): 1.12 (3H, d, J=7.0Hz), 1.21 (3H, d, J=6.5Hz),1.3-1.9 (10H, m), 2.22 (3H, s), 2.37 (3H, s), 3.0-3.6 (5H, m), 3.98 (1H,d, J=16.0Hz), 4.87 (1H, d, J=16.0Hz), 5.09 (1H, d, J=8.5Hz), 6.72 (1H,d, J=6.2Hz), 7.0-7.6 (7H, m), 8.82 (1H, s)

[1939] Mass (APCI)(e/z): 518 (M⁺+1)

EXAMPLE 68

[1940]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-5-cyclopropyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1941] mp: 177.7-179.2° C.

[1942] IR (Nujol, cm⁻¹): 3300, 1660, 1630, 1605

[1943]¹H-NMR (DMSO-d₆, δ): 0.7-1.3 (4H, m), 1.3-1.9 (10H, m), 2.0-2.2(1H, m), 2.22 (3H, s), 2.37 (3H, s), 3.0-3.6 (4H, m), 3.96 (1H, d,J=16.0Hz), 4.90 (1H, d, J=16.0Hz), 5.05 (1H, d, J=8.5Hz), 6.7-6.9 (1H,m), 7.0-7.8 (7H, m), 8.79 (1H, s)

[1944] Mass (APCI)(e/z): 516 (M⁺+1)

EXAMPLE 69

[1945]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-isobutyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1946] mp: 131.6-133.4° C.

[1947] IR (Nujol, cm⁻¹): 3370, 3320, 1700, 1635, 1605

[1948]¹H-NMR (DMSO-d₆, δ): 0.94 (6H, d, J=6.4Hz), 1.3-1.9 (10H, m),2.1-2.3 (1H, m), 2.22 (3H, s), 2.37 (3H, s), 2.68 (2H, d, J=6.7Hz),3.0-3.6 (4H, m), 3.97 (1H, d, J=16.1Hz), 4.88 (1H, d, J=16.1Hz), 5.12(1H, d, J=8.5Hz), 6.72 (1H, d, J=6.3Hz), 7.0-7.6 (7H, m), 8.84 (1H, s)

[1949] Mass (APCI)(e/z): 532 (M⁺+1)

EXAMPLE 70

[1950]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-5-cyclohexyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1951] mp: 153.6-155.3° C.

[1952] IR (Nujol, cm⁻¹): 3360, 3330, 1695, 1650, 1630

[1953]¹H-NMR (DMSO-d₆, δ): 1.1-2.1 (20H, m), 2.22 (3H, s), 3.37 (3H, s),2.8-3.0 (1H, m), 3.0-3.6 (4H, m), 3.98 (1H, d, J=16.0Hz), 4.84 (1H, d,J=16.0Hz), 5.08 (1H, d, J=8.3Hz), 6.7-6.8 (1H, m), 7.0-7.6 (7H, m), 8.83(1H, s)

[1954] Mass (APCI)(e/z): 558 (M⁺+1)

EXAMPLE 71-1

[1955]N-[(3RS)-5-Acetoxymethyl-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 32.

[1956] mp: 112.2-114.2° C.

[1957] IR (Nujol, cm⁻¹): 3330, 1735, 1680, 1640

[1958]¹H-NMR (DMSO-d₆, δ): 1.2-1.8 (10H, m), 2.06 (3H, s), 2.22 (3H, s),2.30 (3H, s), 2.9-3.6 (4H, m), 3.97 (1H, d, J=16Hz), 4.8-5.0 (2H, m),5.18 (1H, d, J=8.4Hz), 5.35 (1H, d, J=16Hz), 6.7-6.8 (1H, m), 7.0-7.2(3H, m), 7.2-7.4 (2H, m), 7.4-7.7 (2H, m), 8.87 (1H, s)

[1959] Mass (APCI)(e/z): 506 (M⁺+1)

EXAMPLE 71-2

[1960]N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-hydroxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Preparation 14.

[1961] mp: 214.5-216.0° C.

[1962] IR (Nujol, cm⁻¹): 3380, 3280, 1690, 1615

[1963]¹H-NMR (DMSO-d₆, δ): 1.2-1.9 (10H, m), 2.22 (3H, s), 2.38 (3H, s),2.9-3.2 (1H, m), 3.2-3.4 (3H, m), 3.99 (1H, d, J=16Hz), 4.56 (1H, s),4.57 (2H, s), 4.97 (1H, d, J=16Hz), 5.22 (1H, d, J=8.5Hz), 6.72 (1H, d,J=6.6Hz), 7.0-7.7 (7H, m), 8.89 (1H, s)

[1964] Mass (APCI)(e/z): 506 (M⁺+1)

EXAMPLE 71-3(1)

[1965] To a solution ofN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-hydroxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(300 mg) and diisopropylethylamine (115 mg) in methylene chloride (4 ml)was added methanesulfonyl chloride (102 mg) under stirring and coolingin an ice-bath. The mixture was stirred under the same conditions for 4hours. A mixture of 50% aqueous dimethylamine (2 ml) and tetrahydrofuran(2 ml) was added to the reaction mixture obtained above and theresultant mixture was stirred under cooling in an ice-bath for 3.5hours. Ethyl acetate and water were added to the reaction mixture. Theseparated organic layer was washed with water and brine, and dried oversodium sulfate. The solvent was evaporated in vacuo to afford a residue,which was triturated in diisopropyl ether and collected by filtration togiveN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-(N,N-dimethylamino)methyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureaas crystalline powder (209 mg, 66.2% yield).

[1966] mp: 147.9-149.1° C.

[1967] IR (Nujol, cm⁻¹): 3450, 1670, 1650, 1610

[1968]¹H-NMR (DMSO-d₆, δ): 1.2-1.9 (10H, m), 2.22 (3H, s), 2.25 (6H, s),2.37 (3H,s), 3.0-3.6 (4H, m), 3.52 (2H, s), 3.97 (1H, d, J=16Hz), 4.86(1H, d, J=16Hz), 5.13 (1H, d, J=8.4Hz), 6.7-6.8 (1H, m), 7.0-7.5 (6H,m), 7.7-7.9 (1H, m), 8.87 (1H, s)

[1969] Mass (APCI)(e/z): 533 (M⁺+1)

EXAMPLE 71-3(2)

[1970] A mixture ofN-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-hydroxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(1.50 mg) and manganese dioxide (15.0 g) in acetone (40 ml) was stirredat ambient temperature for 5 hours. The undissolved substances wereremoved by filtration. The filtrate was evaporated in vacuo to afford aresidue, which was triturated in diisopropyl ether and collected byfiltration to giveN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureaas crystalline powder (1.20 g, 80.2% yield).

[1971] mp: 137.9-141.0° C.

[1972] IR (Nujol, cm⁻¹): 3350, 1710, 1680, 1640

[1973]¹H-NMR (DMSO-d₆, δ): 1.2-1.9 (10H, m), 2.23 (3H, s), 2.39 (3H, s),2.8-3.6 (4H, br), 3.98 (1H, d, J=16Hz), 4.94 (1H, d, J=16Hz), 5.47 (1H,d, J=8.3Hz), 6.7-6.8 (1H, m), 7.0-7.7 (7H, m), 8.97 (1H, s), 9.64 (1H,s)

[1974] Mass (APCI)(e/z): 504 (M⁺+1)

EXAMPLE 72

[1975]N-[(3RS)-1-Cyclooctylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1976] mp: 162.9-164.4° C.

[1977] IR (Nujol, cm⁻¹): 3350, 1720, 1680, 1640, 1605

[1978]¹H-NMR (DMSO-d₆, δ): 1.3-2.0 (14H, m), 2.22 (3H, s), 2.33 (3H, s),2.47 (3H, s), 2.5-2.7 (1H, m), 4.09 (1H, d, J=18Hz), 5.00 (1H, d,J=18Hz), 5.07 (1H, d, J=9.4Hz), 6.7-6.8 (1H, m), 7.0-7.6 (7H, m), 8.85(1H, s)

[1979] Mass (APCI)(e/z): 489 (M⁺+1)

EXAMPLE 73

[1980]N-[(3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-5-isobutyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1981] mp: 152.3-154.8° C.

[1982] IR (Nujol, cm⁻¹): 3410, 3250, 1730, 1680, 1650

[1983]¹H-NMR (DMSO-d₆, δ): 0.94 (6H, d, J=6.6Hz), 1.1-1.4 (5H, m),1.5-2.0 (5H, m), 2.0-2.2 (1H, m), 2.22 (3H, s), 2.32 (3H, s), 3.3-3.6(1H, m), 3.6-3.8 (2H, m), 4.72 (1H, d, J=17.6Hz), 4.89 (1H, d,J=17.6Hz), 5.09 (1H, d, J=8.5Hz), 6.7-6.8 (1H, m), 7.0-7.6 (7H, m), 8.83(1H, s)

[1984] Mass (APCI)(e/z): 503 (M⁺+1)

EXAMPLE 74

[1985]N-{(3RS)-2,3-dihydro-5,9-dimethyl-1-[N-methyl-N-(2-pyridyl)amino]carbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl}-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 59.

[1986] mp: 222.3-224.2° C.

[1987] IR (Nujol, cm⁻¹): 3280, 1680, 1670, 1650

[1988]¹H-NMR (DMSO-d₆, δ): 2.21 (3H, s), 2.25 (3H, s), 3.23 (3H, s),2.47 (3H, s), 4.13 (1H, d, J=17Hz), 4.91 (1H, d, J=17Hz), 5.09 (1H, d,J=7.9Hz), 6.6-6.8 (1H, br), 7.0-7.7 (9H, m), 7.8-8.0 (1H, m), 8.4-8.6(1H, m), 8.91 (1H, s)

[1989] Mass (APCI)(e/z): 485 (M⁺+1)

EXAMPLE 75(1)-1

[1990] To a suspension of sodium hydride (31 mg, 60% in mineral oil) intetrahydrofuran was added ethyl diethylphosphonoacetate (195 mg) understirring and cooling in an ice-bath. After stirring for 15 minutes, asolution ofN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(300 mg) in tetrahydrofuran (5 ml) was added to the reaction mixtureunder the same conditions. The mixture was stirred at ambienttemperature for 4 hours. To a reaction mixture was added 0.1N aqueoushydrochloric acid (20 ml) and the resultant mixture was extracted withethyl acetate. The separated organic layer was washed with water andbrine, and dried over magnesium sulfate. The solvent was evaporated invacuo to afford a residue, which was subjected to column chromatographyon silica gel eluting with a mixture of toluene and ethyl acetate (3:1)to giveN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-((EZ)-2-(ethoxycarbonyl)ethenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(266 mg, 77.8% yield) as crystalline powder.

[1991] mp: 175.2-177.7° C.

[1992] IR (Nujol, cm⁻¹): 3260, 1730, 1700, 1665, 1620

[1993]¹H-NMR (DMSO-d₆, δ): 1.21 (3H, t, J=7.1Hz), 1.2-1.8 (10H, m), 2.27(3H, s), 2.34 (3H, s), 3.0-3.6 (4H, m), 4.10 (2H, q, J=7.1Hz), 3.9-4.1(1H, m), 4.86 (1H, d, J=16Hz), 5.3-5.5 (1H, m), 6.8-6.9 (1H, m), 7.0-7.4(9H, m), 9.54 (1H, s), 10.22 (1H, s)

[1994] Mass (APCI)(e/z): 574 (M⁺+1)

EXAMPLE 75(1)-2

[1995] A mixture ofN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-5-((EZ)-2-(ethoxycarbonyl)ethenyl)-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(230 mg) and 1N sodium hydroxide (1.6 ml) in, 1,2-dimethoxyethane (6.0ml) was stirred at ambient temperature overnight. Ethyl acetate andwater were added to the reaction mixture. The separated aqueous layerwas made acidic with 1N aqueous hydrochloric acid and extracted withethyl acetate. The extract was dried over magnesium sulfate andevaporated in vacuo to afford a residue, which was triturated indiisopropyl ether and collected by filtration to giveN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-((EZ)-2-carboxylethenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(80 mg. 36.6% yield) as crystalline powder.

[1996] mp: 129.3-134.1° C.

[1997] IR (Nujol, cm⁻¹): 3200, 1710, 1660, 1630

[1998]¹H-NMR (DMSO-d₆, δ): 1.2-1.8 (10H, m), 2.34 (3H, s), 2.26 (3H, s),3.0-3.6 (4H, m), 4.05 (1H, d, J=17Hz), 4.86 (1H, d, J=17Hz), 5.4-5.6(1H, m), 6.8-6.9 (1H, m), 7.0-7.4 (9H, m), 10.26 (1H, s)

[1999] Mass (APCI)(e/z): 546 (M⁺+1)

EXAMPLE 75(2)

[2000] A mixture ofN-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(300 mg), hydroxylamine hydrochloride (41 mg) and sodium acetate (51 mg)in acetic acid (1.5 ml) was stirred at ambient temperature for 2.5hours. Acetic anhydride (0.4 ml) was added to the reaction mixture, andthe resultant mixture was stirred at 90° C. for 11.5 hours. After thereaction mixture was allowed to cool to ambient temperature, ethylacetate and aqueous sodium hydrogen carbonate were added into themixture successively under stirring. The separated organic layer waswashed with aqueous sodium hydrogen carbonate and brine, and dried overmagnesium sulfate. The solvent was evaporated in vacuo to afford aresidue, which was subjected to column chromatography on silica geleluting with a mixture of toluene and ethyl acetate (4:1) to giveN-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-5-cyano-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiagepin-3-yl]-N′-(3-methylphenyl)ureaas crystalline powder (80 mg).

[2001] mp: 213.4-216.7° C.

[2002] IR (Nujol, cm⁻¹): 3300, 2210, 1690, 1656

[2003]¹H-NMR (DMSO-d₆, δ): 1.2-1.9 (10H, m), 2.25 (3H, s), 2.38 (3H, s),2.9-3.8 (4H, m), 4.22 (1H, d, J=16Hz), 5.06 (1H, d, J=16Hz), 5.37 (1H,d, J=8.1Hz), 6.7-6.9 (1H, m), 7.0-7.8 (9H, m), 9.4-9.7 (1H, m)

[2004] Mass (APCI)(e/z): 501 (M⁺+1)

EXAMPLE 76(1)

[2005] To a solution of(3S)-3-amino-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(6.30 g) in tetrahydrofuran (100 ml) was added m-tolyl isocyanate (2.62g) under stirring at ambient temperature. The mixture was stirred for 3hours further under the same conditions. After removal of the solvent invacuo, the residue was dissolved in ethyl acetate and washed with adiluted hydrochloric acid, a diluted aqueous sodium bicarbonate andwater successively. The organic extract was dried over magnesium sulfateand evaporated in vacuo to afford an oil (9.36 g), which was subjectedto column chromatography on silica gel eluting with a mixture ofmethylene chloride and methanol (50:1). The fractions containing thedesired product were combined and evaporated in vacuo to giveN-[(3S)-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea(6.34 g, 72.4%) as an amorphous mass.

[2006]¹H-NMR (CDCl₃, δ): 1.05-1.4 (5H, m), 1.26 (3H, t, J=7.4Hz),1.55-1.9 (5H, m), 2.02 (1H, br, s), 2.2-2.35 (1H, m), 2.29 (3H, s), 2.33(3H, s), 2.92 (2H, q, J=7.4Hz), 3.77 (1H, d, J=17.2 Hz), 5.06 (1H, d,J=17.2Hz),5.48(1H, d, J=8.3Hz), 6.7-7.4 (8H, m)

[2007] APCI-MS(m/z): 475 (M⁺+1)

[2008] [α]_(D) ³⁰=−53.36° (C=1.16, CHCl₃)

EXAMPLE 76(2)

[2009]N-[(3R)-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)ureawas obtained in a similar manner to that of Example 76(1).

[2010]¹H-NMR (CDCl₃, δ): 1.05-1.4 (5H, m), 1.26 (3H, t, J=7.4Hz),1.55-1.9 (5H, m), 1.95-2.35 (2H, m), 2.29 (3H, s), 2.32 (3H, s), 2.92(2H, q, J=7.4Hz), 3.77 (1H, d, J=17.2Hz), 5.06 (1H, d, J=17.2 Hz), 5.48(1H, d, J=8.3Hz), 6.7-7.4 (8H, m)

[2011] APCI-MS(m/z): 475 (M⁺+1)

[2012] [α]_(D) ³⁰=−50.92° (C=1.08, CHCl₃)

1. A Compound of the formula:

[Wherein R¹ is (1) lower alkyl; (2) hydroxy(lower)alkyl; (3) protectedhydroxy(lower)alkyl; (4) heterocyclic(lower)alkyl which may have one ormore suitable substituent(s); (5) aryl(lower)alkyl which may have one ormore suitable substituent(s)], (6) carboxy(lower)alkyl; (7) protectedcarboxy(lower)alkyl; or (8)

[wherein A is lower alkylene and R⁵ is (a) lower alkyl, (b) C₃-C₈cycloalkyl, (c) adamantyl, (d) aryl which may have one or more suitablesubstituent(s), (e) amino which may have one or two suitablesubstituent(s) (f) azabicyclo[3.2.2]nonyl, or (g) saturatedheteromonocyclic group containing at least one nitrogen atom, which mayhave one or more suitable substituent(s)], R² is (1) lower alkyl, (2)C₃-C₈ cycloalkyl, (3) lower alkoxy(lower)alkyl, (4) C₃-C₈cycloalkyl(lower)alkyl, (5) N,N-di(lower)alkylamino(lower)alkyl, (6)lower alkylpiperazinyl(lower)alkyl, (7) lower alkylthio(lower)alkyl, (8)hydroxy(lower)alkyl, (9) protected hydroxy(lower)alkyl, (10)azabicyclo[3.2.2]nonyl(lower)alkyl, (11) ary] which may have one or moresuitable substituent(s), (12) cyano, (13) lower alkanoyl, (14)carboxy(lower)alkenyl, or (15) protected carboxy(lower)alkenyl, R³ isindolyl or —NH-R⁶, and R⁴ is (1) hydrogen, (2) lower alkyl, (3) halogen,or (4) di(lower)alkylamino, with proviso that when R⁴ is hydrogen, thenR² is lower alkyl or C₃-C₈ cycloalkyl(lower)alkyl, or a pharmaceuticallyacceptable salt thereof.
 2. A Compound of claim 1, wherein R¹ is (1)lower alkyl; (2) hydroxy(lower)alkyl; (3) acyloxy(lower)alkyl; (4)heterocyclic(lower)alkyl which may have one or more substituent(s)selected from the group consisting of lower alkyl and acyl; (5)aryl(lower)alkyl which may have one or more acyl(s); (6)carboxy(lower)alkyl; (7) esterified carboxy(lower)alkyl; or (8)

[wherein A is lower alkylene and R⁵ is (a) lower alkyl, (b) C₃-C₈cycloalkyl, (c) adamantly, (d) acyl which may have one or moresubstituent(s) (e) selected from the group consisting of lower alkyl,hydroxy, lower alkoxy, carboxy(lower)alkoxy, protectedcarboxy(lower)alkoxy, nitro, amino and diacylamino, (e) amino which mayhave one or two substituent(s) selected from the group consisting oflower alkyl, hydroxy(lower)alkyl, aryl(lower)alkyla and pyridyl, (f)azabicyclo[3.2.2]nonyl, or (g) saturated heteromonocyclic groupcontaining at least one nitrogen atom, which may have one or moresubstituent(s) selected from the group consisting of carbamoyl, acyl,hydroxy, oxo, aryl, aryl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl,di(lower)alkylcarbamoyl, heterocyclic group, andheterocycliccarbonyl(lower)alkyl], R² is (1) lower alkyl, (2) C₃-C₈cycloalkyl, (3) lower alkoxy(lower)alkyl, (4) C₃-C₈cycloalkyl(lower)alkyl, (5) N,N-di(lower)alkylamino(lower)alkyl, (6)lower alkylpiperazinyl(lower)alkyl, (7) lower alkylthio(lower)alkyl, (8)hydroxy(lower)alkyl, (9) acyloxy(lower)alkyl,(10)azabicyclo[3.2.2]nonyl(lower)alkyl, (11) aryl which may have one ormore halogen(s), (12) cyano, (13) lower alkanoyl, (14)carboxy(lower)alkenyl, or (15) esterified carboxy(lower)alkenyl, R³ isindolyl or —NH-R⁶, [wherein R⁶ is (1)aryl which may have one or moresubstituent(s) selected from the group consisting of lower alkyl,hydroxy, lower alkoxy, lower alkylthio, hydroxy(lower)alkyl, acyl,halogen, carboxy, protected carboxy, tetrazolyl,triphenyl(lower)alkyltetrazolyl, hydroxyimino(lower)alkyl,sulfo(lower)alkyl, tetrazolyl(lower)alkyl and di(lower)alkylamino, (2)pyridyl which may have one or more lower alkyl(s), or (3) C₃-C₈cycloalkyl], R⁴ is (1) hydrogen, (2) lower alkyl, (3) halogen or (4)di(lower)alkylamino, with proviso that when R⁴ is hydrogen, then R² islower alkyl or C₃-C₈ cycloalkyl(lower)alkyl, or a pharmaceuticallyacceptable salt thereof.
 3. A compound of claim 1, wherein R¹ is (1)lower alkyl; (2) hydroxy(lower)alkyl; (3) lower alkanoyloxy(lower)alkyl;(4) heterocyclic(lower)alkyl which may have one or more substituent(s)selected from the group consisting of lower alkyl and lower alkanoyl;(5) aryl(lower)alkyl which may have one or more lower alkanoyl(s); (6)carboxy(lower)alkyl; (7) lower alkoxycarbonyl(lower)alkyl; or (8)

[wherein A is lower alkylene and R⁵ is (a) lower alkyl, (b) C₃-C₈cycloalkyl, (c) adamantyl, (d) aryl which may have one or moresubstituent(s) selected from the group consisting of lower alkyl,hydroxy, lower alkoxy, carboxy(lower)alkoxy, loweralkoxycarbonyl(lower)alkoxy, nitro, amino and di(lower alkanoyl)amino,(e) amino which may have one or two substituent(s) selected from thegroup consisting of lower alkyl, hydroxy(lower)alkyl, phenyl(lower)alkyland pyridyl, (f) azabicyclo[3.2.2]nonyl, or (g) saturatedheteromonocyclic group containing at least one nitrogen atom, which mayhave one or more substituent(s) selected from the group consisting ofcarbamoyl, lower alkanoyl, hydroxy, oxo, phenyl, phenyl(lower)alkyl,lower alkyl, hydroxy(lower)alkyl, di(lower)alkylcarbamoyl, piperidyl,pyridyl, pyrimidinyl and pyrrolidinylcarbonyl(lower)alkyl, R² is (1)lower alkyl, (2) C₃-C₈ cycloalkyl, (3) lower alkoxy(lower)alkyl, (4)C₃-C₈ cycloalkyl(lower)alkyl, (5) N,N-di(lower)alkylamino(lower)alkyl,(6) lower alkylpiperazinyl(lower)alkyl, (7) lower alkylthio(lower)alkyl,(8) hydroxy(lower)alkyl, (9) lower alkanoyloxy(lower)alkyl,(10)azabicyclo[3.2.2]nonyl(lower)alkyl, (11) aryl which may have one ormore halogen(s), (12) cyano, (13) lower alkanoyl, (14)carboxy(lower)alkenyl, or (15) lower alkoxycarbonyl(lower)alkenyl, R³ isindolyl or—-NH-R⁶, wherein R⁶ is (1) aryl which may have one or moresubstituent(s) selected from the group consisting of lower alkyl,hydroxy, lower alkoxy, lower alkylthio, hydroxy,(lower)alkyl, loweralkanoyl, halogen, carboxy, esterified carboxy, tetrazolyl,triphenyl(lower)alkyltetrazolyl, hydroxyimino(lower)alkyl,sulfo(lower)alkyl, tetrazoly(lower)alkyl, and di(lower)alkylamido, (2)pyridyl which may have one or more lower alkyl(s), or (3) C₃-C₈cycloalkyl], R⁴ is (1) hydrogen, (2) lower alkyl, (3) halogen or (4)di(lower)alkylamino, with proviso that when R⁴ is hydrogen, then R² islower alkyl or C₃-C₈ cycloalkyl(lower)alkyl, or a pharmaceuticallyacceptable salt thereof.
 4. A compound of claim 1, wherein R¹ is (1)methyl, (2) hydroxyethyl, (3) acetoxyethyl, (4) pyridylmethyl,imidazolylmethyl or thienylmethyl, each of which may have one or moresubstituent(s) selected from the group consisting of methyl and acetyl,(5)benzyl which may have one or more substituent(s) selected from thegroup consisting of acetyl, (6) carboxymethyl, (7) ethoxycarbonylmethylor t-butoxycarbonylmethyl, or (8)

[wherein A is methylene, and R⁵ is (a) methyl, ethyl or t-butyl, (b)cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, (c)adamantyl, (d) phenyl which may have one or more substituent(s) selectedfrom the group consisting of methyl, hydroxy, methoxy, carboxymethoxy,ethoxycarbonylmethoxy, nitro, amino and diacetylamino, (e) amino whichmay have one or two substituent(s) selected from the group consisting ofmethyl, ethyl, t-butyl, isopropyl, 1-methyl-1-phenylethyl and pyridyl,(f) azabicyclo[3.2.2]nonyl, or (g) pyrrolidinyl, piperidyl,azacycloheptyl, azacyclooctyl, piperazinyl or morpholinyl, each of whichmay have one or more substituent(s) selected from the group consistingof carbamoyl, acetyl, hydroxy, oxo, phenyl, benzyl, methyl,hydroxymethyl, hydroxyethyl, diethylcarbamoyl, piperidyl, pyridyl,pyrimidinyl and pyrrolidinylcarbonylmethyl], R² is (1) methyl, ethyl,isopropyl, isobutyl, butyl or isopentyl, (2) cyclopropyl or cyclohexyl,(3) methoxymethyl, (4) cyclohexylmethyl, (5) N,N-dimethylaminomethyl,(6) methylpiperazinylmethyl, (7) methylthiomethyl, (8) hydroxymethyl,(9) acetoxymethyl, (10) (3-azabicyclo[3.2.2]non-3-yl)methyl, (11) phenylwhich may have one or more fluorine(s), (12) cyano, (13) formyl, (14)carboxyvinyl, or (15) ethoxycarbonylvinyl, R³ is indolyl or —NH-R⁶,wherein R⁶ (1)phenyl which may have one or more substituent(s) selectedfrom the group consisting of methyl, hydroxy, methoxy, methylthio,hydroxymethyl, formyl, acetyl, chlorine, bromine, carboxy,t-butoxycarbonyl, tetrazolyl, triphenylmethyltetrazolyl,hydroxyiminomethyl, hydroxyiminoethyl, sulfoethyl, tetrazolylmethyl andN,N-dimethylamino, (2) pyridyl which may have one or more methyl(s), or(3) cyclohexyl], R⁴ is (1) hydrogen, (2) methyl, ethyl or isopropyl, (3)chlorine, or (4) N,N-dimethylamino, with proviso that when R⁴ ishydrogen, then R² is isopropyl, isobutyl, methyl, isopentyl, ethyl,butyl or cyclohexylmethyl, or a pharmaceutically acceptable saltthereof.
 5. A compound of claim 1, which is a compound of the formula:

wherein R² is lower alkyl or C₃-C₈ cycloalkyl, R⁴ is lower alkyl, R⁵ isC₃-C₈ cycloalkyl, R⁶ is lower alkylphenyl and A is lower alkylene, or apharmaceutically acceptable salt thereof.
 6. A compound of claim 1,which is a compound of the formula:

wherein R² is lower alkyl or C₃-C₈ cycloalkyl, R⁴ is lower alkyl, R⁵ isC₃-C₈ cycloalkyl, R⁶ is lower alkylphenyl and A is lower alkylene, or apharmaceutically acceptable salt thereof.
 7. A process for preparing acompound of the formula;

Wherein R¹ is (1) lower alkyl; (2) hydroxy(lower)alkyl; (3) protectedhydroxy(lower)alkyl; (4) heterocyclic(lower)alky which may have one ormore suitable substituent(s); (5) aryl(lower)alkyl which may have one ormore suitable substituent(s); (6) carboxy(lower)alkyl; (7) protectedcarboxy(lower)alkyl; or (8)

[wherein A is lower alkylene and R⁵ is (a) lower alkyl, (b) C₃-C₈cycloalkyl, (c) adamantyl, (d) aryl which may have one or more suitablesubstituent(s), (e) amino which may have one or two suitablesubstituent(s), (f) azabicyclo[3.2.2]nonyl, or (g) saturatedheteromonocyclic group containing at least one nitrogen atom, which mayhave one or more suitable substituent(s)], R² is (1) lower alkyl, (2)C₃-C₈ cycloalkyl, (3) lower alkoxy(lower)alkyl, (4) C₃-C₈cycloalkyl(lower)alkyl, (5) N,N-di(lower)alkylamino(lower)alkyl, (6)lower alkylpiperazinyl(lower)alkyl, (7) lower alkylthio(lower)alkyl, (8)hydroxy(lower)alkyl, (9) protected hydroxy(lower)alkyl, (10)azabicyclo[3.2.2]nonyl(lower)alkyl, (11) aryl which may have one or moresuitable substituent(s), (12) cyano, (13) lower alkanoyl, (14)carboxy(lower)alkenyl, or (15) esterified carboxy(lower)alkenyl, R³ isindolyl or —NH-R⁶, and substituent(s), or R⁴ is (1) hydrogen, (2) loweralkyl, (3) halogen, or (4) di(lower)alkylamino, with proviso that whenR⁴ is hydrogen, then R² is lower alkyl or C₃-C₈ cycloalkyl(lower)alkyl,or a salt thereof, which comprises, (1) reacting a compound of theformula (II):

wherein R¹, R² and R⁴ are each as defined above, or its reactivederivatives at the amino group or a salt thereof with a compound of theformula (III):

wherein R³ is each as defined above, or its reactive derivative or asalt thereof to give a compound of the formula (I):

wherein R¹, R², R³ and R⁴ are each as defined above, or a salt thereof,(2) reacting a compound of the formula (IV):

wherein R², R³, and R⁴ are each as defined above, or a salt thereof witha compound of the formula (V): X-R¹  (V) wherein R¹ is as defined above,X is halogen,or a salt thereof to give a compound of the formula (I):

wherein R¹, R², R³ and R⁴ are each as defined above, or a salt thereof,(3) reacting a compound of the formula (VI):

wherein R², R³, R⁴ and A are each as defined above, or its reactivederivative at the carboxy group or a salt thereof with a compound of theformula (VII):

wherein

is saturated heteromonocyclic group containing at least one nitrogenatom, which may have one or more suitable substituent(s) or its reactivederivative at the imino group or salt thereof to give a compound of theformula (Ia):

wherein R², R³, R⁴, A and

are each as defined above, or a salt thereof, or (4) reacting a compoundof the formula (VI):

wherein R², R³, R⁴ and A are each as defined above, or its reactivederivative at the carboxy group or a salt thereof with a compound of theformula (VIII):

wherein R⁷ is hydrogen, lower alkyl, or hydroxy(lower)alkyl, R⁸ is loweralkyl, hydroxy(lower)alkyl, aryl(lower)alkyl or pyridyl, or its reactivederivative at the imino group or a salt thereof to give a compound ofthe formula (Ib):

wherein R², R³, R⁴, R⁷, R⁸ and A are each as defined above, or a saltthereof.
 8. A pharmaceutical composition which comprises, as an activeingredient, a compound of claim 1 or a pharmaceutically acceptable saltthereof in admixture with pharmaceutically acceptable carriers.
 9. A useof compound of claim 1 or a pharmaceutically acceptable salt thereof asa cholecystokinin antagonist.
 10. A method for treating or preventingcholecystokinin-mediated diseases which comprises administering acompound of claim 1 or a pharmaceutically acceptable salt thereof tohuman or animals.
 11. A process for preparing a pharmaceuticalcomposition which comprises admixing a compound of claim 1 or apharmaceutically acceptable salt thereof with a pharmaceuticallyacceptable carrier.